Point mutations in TRK inhibitor-resistant cancer and methods relating to the same

ABSTRACT

Provided herein are methods of treating a subject having a cancer, methods of selecting a treatment for a subject having a cancer, methods of selecting a subject having a cancer for a treatment that does not include a Trk inhibitor, methods of determining the likelihood that a subject having a cancer will have a positive response to a treatment with a Trk inhibitor, methods of predicting the efficacy of a Trk inhibitor in a subject having cancer, methods of determining a subject&#39;s risk for developing a Trk inhibitor-resistant cancer, and methods of determining the presence of a Trk inhibitor-resistant cancer in a subject, based on the detection of a cell from a sample from the subject that has at least one of the the point mutations in NTRK1 and/or NTRK2 and/or NTRK3.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/335,378, filed Oct. 26, 2016, which claims priority to U.S.Provisional Application Ser. No. 62/246,580, filed on Oct. 26, 2015,62/287,778, filed on Jan. 27, 2016, and 62/323,586, filed on Apr. 15,2016, each of which is herein incorporated by reference in its entirety.

TECHNICAL FIELD

This invention relates to methods of genetics, pharmacogenetics, andcancer biology.

BACKGROUND

Tropomyosin-related kinase (TRK) is a receptor tyrosine kinase family ofneurotrophin receptors that are found in multiple tissues types. Threemembers of the TRK proto-oncogene family have been described: TrkA,TrkB, and TrkC, encoded by the NTRK1, NTRK2, and NTRK3 genes,respectively. The TRK receptor family is involved in neuronaldevelopment, including the growth and function of neuronal synapses,memory development, and maintenance, and the protection of neurons afterischemia or other types of injury (Nakagawara, Cancer Lett. 169:107-114,2001).

TRK was originally identified from a colorectal cancer cell line as anoncogene fusion containing 5′ sequences from tropomyosin-3 (TPM3) geneand the kinase domain encoded by the 3′ region of the neurotrophictyrosine kinase, receptor, type 1 gene (NTRK1) (Pulciani et al., Nature300:539-542, 1982; Martin-Zanca et al., Nature 319:743-748, 1986). TRKgene fusions follow the well-established paradigm of other oncogenicfusions, such as those involving ALK and ROS1, which have been shown todrive the growth of tumors and can be successfully inhibited in theclinic by targeted drugs (Shaw et al., New Engl. J Med 371:1963-1971,2014; Shaw et al., New Engl. J. Med. 370:1189-1197, 2014). Oncogenic TRKfusions induce cancer cell proliferation and engage criticalcancer-related downstream signaling pathways such as mitogen activatedprotein kinase (MAPK) and AKT (Vaishnavi et al., Cancer Discov. 5:25-34,2015). Numerous oncogenic rearrangements involving NTRK1 and its relatedTRK family members NTRK2 and NTRK3 have been described (Vaishnavi etal., Cancer Disc. 5:25-34, 2015; Vaishnavi et al., Nature Med.19:1469-1472, 2013). Although there are numerous different 5′ genefusion partners identified, all share an in-frame, intact TRK kinasedomain. A variety of different Trk inhibitors have been developed totreat cancer (see, e.g., U.S. Patent Application Publication No.62/080,374, International Application Publication Nos. WO 11/006074, WO11/146336, WO 10/033941, and WO 10/048314, and U.S. Pat. Nos. 8,933,084,8,791,123, 8,637,516, 8,513,263, 8,450,322, 7,615,383, 7,384,632,6,153,189, 6,027,927, 6,025,166, 5,910,574, 5,877,016, and 5,844,092).

SUMMARY

The present invention is based on the discovery of Trkinhibitor-resistance NTRK1, NTRK2, and NTRK3 mutations. In view of thisdiscovery, provided herein are methods of treating a subject having acancer, methods of selecting a treatment for a subject having a cancer,methods of selecting a subject having a cancer for a treatment that doesnot include a Trk inhibitor, methods of determining the likelihood thata subject having a cancer will have a positive response to a treatmentwith a Trk inhibitor, methods of predicting the efficacy of a Trkinhibitor in a subject having cancer, methods of determining a subject'srisk for developing a Trk inhibitor-resistant cancer, and methods ofdetermining the presence of a Trk inhibitor-resistant cancer in asubject. In some embodiments, the methods provided herein are based, inpart, on a determination of whether the subject has a cell that has (i)at least one point mutation in a NTRK1 gene that results in theexpression of a TrkA protein comprising a mutation at one or more aminoacid position(s) selected from the group consisting of: 517, 542, 568,573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and 676, and/or (ii)at least one point mutation in a NTRK2 gene that results in theexpression of a TrkB protein comprising a mutation at one or more aminoacid position(s) selected from the group consisting of: 545, 570, 596,601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702, and/or (iii)at least one point mutation in a NTRK3 gene that results in theexpression of a TrkC protein comprising a mutation at one or more aminoacid position(s) selected from the group consisting of: 545, 570, 596,601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and 705. Also providedare kits that allow for the detection of at least one of the pointmutations in NTRK1 and/or NTRK2 and/or NTRK3.

Detection and identification of a subject having cells having a Trkinhibitor-resistant mutation as described herein (e.g., (i) at least onepoint mutation in a NTRK1 gene that results in the expression of a TrkAprotein comprising a mutation at one or more amino acid position(s)selected from the group consisting of: 517, 542, 568, 573, 589, 595,599, 600, 602, 646, 656, 657, 667, and 676, and/or (ii) at least onepoint mutation in a NTRK2 gene that results in the expression of a TrkBprotein comprising a mutation at one or more amino acid position(s)selected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 672, 682, 683, 693, and 702, and/or (iii) at least onepoint mutation in a NTRK3 gene that results in the expression of a TrkCprotein comprising a mutation at one or more amino acid position(s)selected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 675, 685, 686, 696, and 705) can improve treatment of thesubject by, for example, changing the treatment regimen (e.g., changingthe Trk inhibitor administered to the subject or adding an additionalanticancer agent or anticancer therapy) or by administering a Trkinhibitor that is effective in the presence of a Trk inhibitor-resistantmutation (e.g., one or more of the compounds of Table 5, or apharmaceutically acceptable salt thereof).

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein or known in the art) that include:identifying a subject having a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3); and administering to the identified subject a treatment thatdoes not include a first Trk inhibitor as a monotherapy.

Also provided herein are methods of treating a subject having a cancer(e.g., any of the cancers described herein or known in the art) thatinclude: identifying a subject having a cancer cell that has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3); and administering to the identified subject atreatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof.

Also provided herein are methods of treating a subject having a cancer(e.g., any of the cancers described herein or known in the art) thatinclude: identifying a subject having a cancer cell that has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3); and administering to the identified subject atreatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, and another anticancer agentor anticancer therapy.

Also provided herein are methods of treating a subject identified ashaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3) that include:administering to the subject a treatment that does not include a firstTrk inhibitor as a monotherapy.

Also provided herein are methods of treating a subject identified ashaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3) that includeadministering to the subject a treatment that includes one or morecompounds of Table 5, or a pharmaceutically acceptable salt thereof.

Also provided herein are methods of treating a subject identified ashaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3) that includeadministering to the subject a treatment that includes one or morecompounds of Table 5, or a pharmaceutically acceptable salt thereof, andanother anticancer agent or anticancer therapy.

Also provided herein are methods of treating a subject that includeadministering a therapeutically effective amount of a treatment thatdoes not include a first Trk inhibitor as a monotherapy, to a subjecthaving a clinical record that indicates that the subject has a cancercell that has at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3).

Also provided herein are methods of treating a subject that includeadministering a therapeutically effective amount of a treatment thatincludes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, to a subject having a clinical record thatindicates that the subject has a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3).

Also provided herein are methods of treating a subject that includeadministering a therapeutically effective amount of a treatment thatincludes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, and another anticancer agent or anticancertherapy, to a subject having a clinical record that indicates that thesubject has a cancer cell that has at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancerthat include: (a) administering one or more doses of a first Trkinhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and (c) administering a secondTrk inhibitor or a treatment that does not include the first Trkinhibitor of step (a) as a monotherapy to a subject having a cancer cellthat has at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); or (d) administering additionaldoses of the first Trk inhibitor of step (a) to a subject having acancer cell that does not have at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancer,that include: (a) administering one or more doses of a first Trkinhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and (c) administering a treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, to a subject having a cancer cell that has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more of the amino acid positionsshown in Tables 1, 2, or 3); or (d) administering additional doses ofthe first Trk inhibitor to a subject having a cancer cell that does nothave at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancerthat include: (a) administering one or more doses of a first Trkinhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas (i) at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and (c) administering a treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, and another anticancer agent or anticancertherapy to a subject having a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3); or (d) administering additional doses of the first Trkinhibitor to a subject having a cancer cell that does not have at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancer,that include: (a) determining whether a cancer cell in a sample obtainedfrom a subject having a cancer and previously administered one or moredoses of a first Trk inhibitor has at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3); and (b)administering a second Trk inhibitor or a treatment that does notinclude the first Trk inhibitor of step (a) as a monotherapy to asubject having a cancer cell that has at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3); or (c)administering additional doses of the Trk inhibitor of step (a) to asubject having a cancer cell that does not have at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3).

Some embodiments of these methods include administering a second Trkinhibitor or a treatment that does not include the first Trk inhibitorof step (a) as a monotherapy to a subject having a cancer cell that hasat least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3). Some embodiments of these methodsinclude administering additional doses of the first Trk inhibitor ofstep (a) to a subject having a cancer cell that does not have at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancerthat include: (a) determining whether a cancer cell in a sample obtainedfrom a subject having a cancer and previously administered one or moredoses of a first Trk inhibitor has at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3); (b)administering a treatment that includes one or more compounds of Table5, or a pharmaceutically acceptable salt thereof, to a subject having acancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3); or (c) administeringadditional doses of the first Trk inhibitor to a subject having a cancercell that does not have at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancer,that include: (a) determining whether a cancer cell in a sample obtainedfrom a subject having a cancer and previously administered one or moredoses of a first Trk inhibitor, has at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3); (b)administering a treatment that includes one or more compounds of Table5, or a pharmaceutically acceptable salt thereof, and another anticanceragent or anticancer therapy to a subject having a cancer cell that hasat least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); or (c) administering additionaldoses of the first Trk inhibitor to a subject having a cancer cell thatdoes not have at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer (e.g., any of the cancers described herein or known inthe art) that include: identifying a subject having a cancer cell thathas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and selecting a treatment thatdoes not include a first Trk inhibitor as a monotherapy for theidentified subject.

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer (e.g., any of the cancers described herein or known inthe art) that include: identifying a subject having a cancer cell thathas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and selecting a treatment thatincludes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, for the identified subject.

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer (e.g., any of the cancers described herein or known inthe art) that include: identifying a subject having a cancer cell thathas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and selecting a treatment thatincludes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, and another anticancer agent or anticancertherapy for the identified subject.

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that include: selecting a treatment that does notinclude a first Trk inhibitor as a monotherapy for a subject identifiedas having a cancer cell that has at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that include: selecting a treatment that includes one ormore compounds of Table 5, or a pharmaceutically acceptable saltthereof, for a subject identified as having a cancer cell that has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more of the amino acid positionsshown in Tables 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that include: selecting a treatment that includes one ormore compounds of Table 5, or a pharmaceutically acceptable saltthereof, and another anticancer agent or anticancer therapy for asubject identified as having a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3).

Also provided herein are methods of selecting a subject having a cancerfor a treatment that does not include a first Trk inhibitor as amonotherapy, that include: identifying a subject having a cancer cellthat has at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and selecting the identifiedsubject for a treatment that does not include a first Trk inhibitor as amonotherapy.

Also provided herein are methods of selecting a subject having a cancerfor a treatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, that include: identifying asubject having a cancer cell that has at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3); andselecting the identified subject for a treatment that includes one ormore compounds of Table 5, or a pharmaceutically acceptable saltthereof.

Also provided herein are methods of selecting a subject having a cancerfor a treatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, and another anticancer agentor anticancer therapy that include: identifying a subject having acancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3); and selecting theidentified subject for a treatment that includes one or more compoundsof Table 5, or a pharmaceutically acceptable salt thereof, and anotheranticancer agent or anticancer therapy.

Also provided herein are methods of selecting a subject having a cancerfor a treatment that does not include a first Trk inhibitor as amonotherapy, that include: selecting a subject identified as having acancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3), for a treatment thatdoes not include a first Trk inhibitor as a monotherapy.

Also provided herein are methods of selecting a subject having a cancerfor a treatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, that include: selecting asubject identified as having a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3), for a treatment that includes one or more compounds of Table5, or a pharmaceutically acceptable salt thereof.

Also provided herein are methods of selecting a subject having a cancerfor a treatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, and another anticancer agentor anticancer therapy that include: selecting a subject identified ashaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3); and selecting theidentified subject for a treatment that includes one or more compoundsof Table 5, or a pharmaceutically acceptable salt thereof, and anotheranticancer agent or anticancer therapy.

Some embodiments of these methods further include administering theselected treatment to the identified subject.

Some embodiments of these methods further include recording the selectedtreatment in the identified subject's clinical record (e.g., a computerreadable medium). For example, recording that the subject is selectedfor a treatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof. In some embodiments, thesemethods further include recording that the subject is selected for atreatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, and another anticancer agentor anticancer therapy in the subject's clinical record (e.g., a computerreadable medium). In some embodiments, these methods further includerecording that the subject is selected for a treatment that does notinclude a first Trk inhibitor as a monotherapy in the subject's clinicalrecord (e.g., a computer readable medium).

Also provided herein are methods of determining the likelihood that asubject having a cancer will have a positive response to treatment witha first Trk inhibitor as a monotherapy, that include: determiningwhether a cancer cell in a sample obtained from the subject has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3); and determining that a subject having a cancer cellthat has at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3) has a decreased likelihood ofhaving a positive response to treatment with a first Trk inhibitor as amonotherapy.

Also provided herein are methods of determining the likelihood that asubject having a cancer will have a positive response to treatment thatincludes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, that include: determining whether a cancer cellin a sample obtained from the subject has at least one point mutation ina NTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3); anddetermining that a subject having a cancer cell that has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more of the amino acid positions shown in Tables 1,2, or 3) has an increased likelihood of having a positive response totreatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof.

Also provided herein are methods of determining the likelihood that asubject having cancer will have a positive response to treatment with afirst Trk inhibitor as a monotherapy, that include: determining that asubject having a cancer cell that has at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3) has adecreased likelihood of having a positive response to treatment with afirst Trk inhibitor as a monotherapy.

Also provided herein are methods of determining the likelihood that asubject having cancer will have a positive response to treatment thatincludes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, that include: determining that a subject havinga cancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3), has an increasedlikelihood of having a positive response to treatment including one ormore compounds of Table 5, or a pharmaceutically acceptable saltthereof.

Some embodiments of these methods further include: administering atreatment not including a first Trk inhibitor as a monotherapy to thesubject determined to have a decreased likelihood of having a positiveresponse to treatment with a first Trk inhibitor as a monotherapy. Someembodiments of these methods further include: administering a treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, to the subject determined to have an increasedlikelihood of having a positive response to treatment including one ormore compounds of Table 5, or a pharmaceutically acceptable saltthereof.

Also provided herein are methods of predicting the efficacy of treatmentwith a first Trk inhibitor as a monotherapy in a subject having cancer,that include: determining whether a cancer cell in a sample obtainedfrom the subject has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3); and determining thattreatment with a first Trk inhibitor as a monotherapy is less likely tobe effective in a subject having a cancer cell in a sample obtained fromthe subject that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of predicting the efficacy of treatmentwith a treatment including one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, in a subject having cancer,that include: determining whether a cancer cell in a sample obtainedfrom the subject has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3); and determining thattreatment including one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, is more likely to be effectivein a subject having a cancer cell in a sample obtained from the subjectthat has at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3).

Also provided herein are methods of predicting the efficacy of treatmentwith a first Trk inhibitor as a monotherapy in a subject having cancer,that include: determining that treatment with a first Trk inhibitor as amonotherapy is less likely to be effective in a subject having a cancercell in a sample obtained from the subject that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3). Some embodiments of these methods further includeadministering a treatment not including a first Trk inhibitor as amonotherapy to the subject.

Also provided herein are methods of predicting the efficacy of treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, in a subject having cancer, that include:determining that treatment including one or more compounds of Table 5,or a pharmaceutically acceptable salt thereof, is more likely to beeffective in a subject having a cancer cell in a sample obtained fromthe subject that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3). Some embodiments ofthese methods further include administering one or more compound ofTable 5, or a pharmaceutically acceptable salt thereof, to the subject.

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that include: (a) administering one or more doses of afirst Trk inhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and (c) selecting a second Trkinhibitor or a treatment that does not include the first Trk inhibitorof step (a) as a monotherapy for a subject having a cancer cell that hasat least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); or (d) selecting additional dosesof the first Trk inhibitor of step (a) for a subject having a cancercell that does not have at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer, that include: (a) administering one or more doses of afirst Trk inhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and (c) selecting a treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, for a subject having a cancer cell that has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more of the amino acid positionsshown in Tables 1, 2, or 3); or (d) selecting additional doses of thefirst Trk inhibitor for a subject having a cancer cell that does nothave at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer, that include: (a) administering one or more doses of afirst Trk inhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and (c) selecting a treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, and another anticancer agent or anticancertherapy for a subject having a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3); or (d) selecting additional doses of the first Trk inhibitorfor a subject having a cancer cell that does not have at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that includes: (a) determining whether a cancer cell ina sample obtained from a subject having a cancer and previouslyadministered one or more doses of a first Trk inhibitor, has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3); (b) selecting a second Trk inhibitor or a treatmentthat does not include the first Trk inhibitor of step (a) as amonotherapy to a subject having a cancer cell that has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more of the amino acid positions shown in Tables 1,2, or 3); or (c) selecting additional doses of the first Trk inhibitorof step (a) to a subject having a cancer cell that does not have atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more of the amino acid positionsshown in Tables 1, 2, or 3).

Some embodiments of these methods include selecting a second Trkinhibitor or a treatment that does not include the first Trk inhibitorof step (a) as a monotherapy for a subject having a cancer cell that hasat least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3). Some embodiments of these methodsinclude selecting additional doses of the first Trk inhibitor of step(a) for a subject having a cancer cell that does not have (at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more of the amino acid positions shown in Tables 1,2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer, that include: (a) determining whether a cancer cell ina sample obtained from a subject having a cancer and previouslyadministered one or more doses of a first Trk inhibitor, has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3); (b) selecting a treatment that includes one or morecompounds of Table 5, or a pharmaceutically acceptable salt thereof, toa subject having a cancer cell that has at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3); or (c)selecting additional doses of the first Trk inhibitor to a subjecthaving a cancer cell that does not have at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer, that include: (a) determining whether a cancer cell ina sample obtained from a subject having a cancer and previouslyadministered one or more doses of a first Trk inhibitor, has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3); (b) selecting a treatment that includes one or morecompounds of Table 5, or a pharmaceutically acceptable salt thereof, andanother anticancer agent or anticancer therapy to a subject having acancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3); or (c) selectingadditional doses of the first Trk inhibitor to a subject having a cancercell that does not have at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3).

Some embodiments of any of the methods described herein further includerecording the selected treatment in the subject's clinical record (e.g.,a computer readable medium). Some embodiments of any of the methodsdescribed herein further include administering selected treatment to thesubject.

In some embodiments of any of the methods described herein, the subjectis previously identified or diagnosed as having the cancer.

In some embodiments of the methods described herein, the treatment thatdoes not include a first Trk inhibitor as a monotherapy is selected froma treatment that includes one or more of: surgery, radiation therapy,chemotherapy, immunotherapy, hormone therapy, small molecule drugstargeting other kinases in a Trk-signaling pathway, recombinantantibodies, and stem cell transplant. In some embodiments of the methodsdescribed herein, the treatment that does not include a first Trkinhibitor as a monotherapy includes: one or more of surgery, radiationtherapy, chemotherapy, immunotherapy, hormone therapy, small moleculedrugs targeting other kinases in a Trk-signaling pathway, recombinantantibodies, and stem cell transplant; and one or more Trk inhibitors. Insome embodiments of the methods described herein, the treatment thatdoes not include a first Trk inhibitor as a monotherapy includes one ormore compounds of Table 5, or a pharmaceutically acceptable saltthereof, as a monotherapy.

Also provided herein are methods of determining a subject's risk fordeveloping a Trk inhibitor-resistant cancer that include: determiningwhether a cell in a sample obtained from the subject has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more of the amino acid positions shown in Tables 1,2, or 3); and identifying a subject having a cell that has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more of the amino acid positions shown in Tables 1,2, or 3), as having an increased likelihood of developing a Trkinhibitor-resistant cancer. Also provided herein are methods ofdetermining a subject's risk for developing a Trk inhibitor-resistantcancer that include: identifying a subject having a cell that has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more of the amino acid positionsshown in Tables 1, 2, or 3), as having an increased likelihood ofdeveloping a Trk inhibitor-resistant cancer. Some embodiments of thesemethods further include confirming a diagnosis of a Trkinhibitor-resistant cancer in a subject determined to have an increasedlikelihood of developing a Trk inhibitor-resistant cancer.

Also provided herein are methods of determining the presence of a Trkinhibitor-resistant cancer in a subject that include: determiningwhether a cancer cell in a sample obtained from the subject has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3); and determining that a subject having a cancer cellthat has at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3), has an a Trk inhibitor-resistantcancer. Also provided herein are methods of determining the presence ofa Trk inhibitor-resistant cancer in a subject that include: determiningthat a subject having a cancer cell that has at least one point mutationin a NTRK gene that results in the expression of a Trk protein includinga mutation at one or more amino acid positions (e.g., a mutation at oneor more of the amino acid positions shown in Tables 1, 2, or 3).

In some embodiments of any of the methods described herein, the firstTrk inhibitor (e.g., the first Trk inhibitor in step (a)) is selectedfrom the group consisting of: entrectinib(N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide);(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate; cabozantinib((N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide));dovatinib(4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-onemono 2-hydroxypropanoate hydrate); belizatinib(4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)benzamide);sitravatinib(N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyppyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);PLX7486; altiratinib(N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);AZD7451((S)—N-(1-(5-fluoropyrimidin-2-yl)ethyl)-3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine).In some embodiments, the first Trk inhibitor (e.g., the first Trkinhibitor in step (a)) is entrectinib. In some embodiments, the firstTrk inhibitor (e.g., the first Trk inhibitor in step (a)) is thecompound of Formula I:

or a hydrogen sulfate salt thereof. In some embodiments, the first Trkinhibitor (e.g., the first Trk inhibitor in step (a)) is a crystallineform of the compound of Formula I or a hydrogen sulfate salt thereof(e.g., a compound of Formula I-HS).

In some embodiments of any of the methods described herein, the secondTrk inhibitor is selected from the group consisting of: a(R)-2-phenylpyrrolidine substituted imadazopyridazine, AZD6918,GNF-4256, GTx-186, GNF-5837, AZ623, AG-879, altiratinib, CT327,ARRY-470, AR-772, AR-523, AR-786, AR-256, AR-618, AZ-23, AZD7451,cabozantinib, CEP-701, CEP-751, PHA-739358, dovitinib, entrectinib(N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide),PLX7486, Gö 6976, GW441756, MGCD516, ONO-5390556, PHA-848125AC,regorafenib, sorafenib, sunitinib, TSR-011, VM-902A, K252a, a4-aminopyrazolylpyrimidine, and a substituted pyrazolo[1,5-a] pyrimidinecompound. In some embodiments of any of the methods described herein,the second Trk inhibitor is selected from the compounds of Table 5, or apharmaceutically acceptable salt thereof.

In some embodiments of any of the methods described herein, the subjectis suspected of having a cancer. In some embodiments of any of themethods described herein, the subject has one or more symptoms ofcancer. In some embodiments of any of the methods described herein, thesubject is previously identified or diagnosed as having a cancer.

In some embodiments of any of the methods described herein, the step ofdetermining whether a cell in a sample obtained from the subject has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more of the amino acid positionsshown in Tables 1, 2, or 3), comprises performing an assay to determinethe presence of the at least one point mutation in a NTRK1 gene and/or aNTRK2 gene and/or a NTRK3 gene in a cell in the sample. In someembodiments of any of the methods described herein, the step ofdetermining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3), comprises performing an assay todetermine the presence of the at least one point mutation in a NTRK1gene and/or a NTRK2 gene and/or a NTRK3 gene in a cancer cell in thesample. In some embodiments of any of the methods described herein, theassay is selected from the group consisting of: denaturing gradient gelelectrophoresis (DGGE), temperature gradient gel electrophoresis (TGGE),temperature gradient capillary electrophoresis, a single strandconformational polymorphism assay, a molecular beacon assay, a dynamichybridization assay, a PCR-based assay, denaturing high performanceliquid chromatography. In some embodiments of any of the methodsdescribed herein, the assay includes sequencing a segment of the NTRK1gene and/or the NTRK2 gene and/or the NTRK3 gene including the at leastone point mutation.

In some embodiments of any of the methods described herein, the canceris selected from the group consisting of: adenocarcinoma, adrenal glandcortical carcinoma, adrenal gland neuroblastoma, anus squamous cellcarcinoma, appendix adenocarcinoma, bladder urothelial carcinoma, bileduct adenocarcinoma, bladder carcinoma, bladder urothelial carcinoma,bone chordoma, bone marrow leukemia lymphocytic chronic, bone marrowleukemia non-lymphocytic acute myelocytic, bone marrow lymphproliferative disease, bone marrow multiple myeloma, bone sarcoma, brainastrocytoma, brain glioblastoma, brain medulloblastoma, brainmeningioma, brain oligodendroglioma, breast adenoid cystic carcinoma,breast carcinoma, breast ductal carcinoma in situ, breast invasiveductal carcinoma, breast invasive lobular carcinoma, breast metaplasticcarcinoma, cervix neuroendocrine carcinoma, cervix squamous cellcarcinoma, colon adenocarcinoma, colon carcinoid tumor, duodenumadenocarcinoma, endometrioid tumor, esophagus adenocarcinoma, eyeintraocular melanoma, eye intraocular squamous cell carcinoma, eyelacrimal duct carcinoma, fallopian tube serous carcinoma, gallbladderadenocarcinoma, gallbladder glomus tumor, gastroesophageal junctionadenocarcinoma, head and neck adenoid cystic carcinoma, head and neckcarcinoma, head and neck neuroblastoma, head and neck squamous cellcarcinoma, kidney chromophore carcinoma, kidney medullary carcinoma,kidney renal cell carcinoma, kidney renal papillary carcinoma, kidneysarcomatoid carcinoma, kidney urothelial carcinoma, leukemialymphocytic, liver cholangiocarcinoma, liver hepatocellular carcinoma,lung adenocarcinoma, lung adenosquamous carcinoma, lung atypicalcarcinoid, lung carcinosarcoma, lung large cell neuroendocrinecarcinoma, lung non-small cell lung carcinoma, lung sarcoma, lungsarcomatoid carcinoma, lung small cell carcinoma, lung small cellundifferentiated carcinoma, lung squamous cell carcinoma, lymph nodelymphoma diffuse large B cell, lymph node lymphoma follicular lymphoma,lymph node lymphoma mediastinal B-cell, lymph node lymphomaplasmablastic lung adenocarcinoma, lymphoma follicular lymphoma,non-Hodgkin's lymphoma, nasopharynx and paranasal sinusesundifferentiated carcinoma, ovary carcinoma, ovary carcinosarcoma, ovaryclear cell carcinoma, ovary epithelial carcinoma, ovary granulosa celltumor, ovary serous carcinoma, pancreas carcinoma, pancreas ductaladenocarcinoma, pancreas neuroendocrine carcinoma, peritoneummesothelioma, peritoneum serous carcinoma, placenta choriocarcinoma,pleura mesothelioma, prostate acinar adenocarcinoma, prostate carcinoma,rectum adenocarcinoma, rectum squamous cell carcinoma, skin adnexalcarcinoma, skin basal cell carcinoma, skin melanoma, skin Merkel cellcarcinoma, skin squamous cell carcinoma, small intestine adenocarcinoma,small intestine gastrointestinal stromal tumors (GISTs), soft tissueangiosarcoma, soft tissue Ewing sarcoma, soft tissuehemangioendothelioma, soft tissue inflammatory myofibroblastic tumor,soft tissue leiomyosarcoma, soft tissue liposarcoma, soft tissueneuroblastoma, soft tissue paraganglioma, soft tissue perivascularepitheliod cell tumor, soft tissue sarcoma, soft tissue synovialsarcoma, stomach adenocarcinoma, stomach adenocarcinoma diffuse-type,stomach adenocarcinoma intestinal type, stomach adenocarcinomaintestinal type, stomach leiomyosarcoma, thymus carcinoma, thymusthymoma lymphocytic, thyroid papillary carcinoma, unknown primaryadenocarcinoma, unknown primary carcinoma, unknown primary malignantneoplasm, unknown primary melanoma, unknown primary sarcomatoidcarcinoma, unknown primary squamous cell carcinoma, unknownundifferentiated neuroendocrine carcinoma, unknown primaryundifferentiated small cell carcinoma, uterus carcinosarcoma, uterusendometrial adenocarcinoma, uterus endometrial adenocarcinomaendometrioid, uterus endometrial adenocarcinoma papillary serous, anduterus leiomyosarcoma.

In some of embodiments of any of the methods described herein, the atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions can be selected from (i) at least one point mutation in aNTRK1 gene that results in the expression of a TrkA protein including amutation at one or more amino acid position(s) selected from the groupconsisting of: 517, 542, 568, 573, 589, 595, 599, 600, 602, 646, 656,657, 667, and 676, and/or (ii) at least one point mutation in a NTRK2gene that results in the expression of a TrkB protein including amutation at one or more amino acid position(s) selected from the groupconsisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 672, 682,683, 693, and 702, and/or (iii) at least one point mutation in a NTRK3gene that results in the expression of a TrkC protein including amutation at one or more amino acid position(s) selected from the groupconsisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685,686, 696, and 705. In some embodiments of any of the methods describedherein, the TrkA protein includes one or more of the following aminoacid substitutions: G517R, A542V, V573M, F589L, F589C, G595S, G595R,D596V, F600L, F646V, C656Y, C656F, L657V, G667S, G667C, and Y676S. Insome embodiments of any of the methods described herein, the TrkBprotein includes one or more of the following amino acid substitutions:G545R, A570V, Q596E, Q596P, V601G, F617L, F617C, F617I, G623S, G623R,D624V, R630K, C682Y, C682F, L683V, G693S, and G713S. In some embodimentsof any of the methods described herein, the TrkC protein includes one ormore of the following amino acid substitutions: G545R, A570V, F617L,G623R, D624V, C685Y, C685F, L686V, and G696A.

Also provided are kits that include: one or more probes that eachspecifically hybridize to a segment of a NTRK1 gene that encodes amutation at one of amino acid positions 517, 542, 568, 573, 589, 595,599, 600, 602, 646, 656, 657, 667, and 676 in TrkA protein; and/or oneor more probes that each specifically hybridize to a segment of a NTRK2gene that encodes a mutation at one of amino acid positions 545, 570,596, 601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702 in TrkBprotein; and/or one or more probes that each specifically hybridize to asegment of a NTRK3 gene that encodes a mutation at one or amino acidpositions 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685, 686,696, and 705 in TrkC protein. Some embodiments of these kits include:one or more probes that each specifically hybridize to a segment of aNTRK1 gene that encodes a mutation selected from the group consistingof: G517R, A542V, V573M, F589L, F589C, G595S, G595R, D596V, F600L,F646V, C656Y, C656F, L657V, G667S, G667C, and Y676S in TrkA protein;and/or one or more probes that each specifically hybridize to a segmentof a NTRK2 gene that encodes a mutation selected from the groupconsisting of: G545R, A570V, Q596E, Q596P, V601G, F617L, F617C, F617I,G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S, and G713S inTrkB protein; and/or one or more probes that each specifically hybridizeto a segment of a NTRK3 gene that encodes a mutation selected from thegroup consisting of: G545R, A570V, F617L, G623R, D624V, C685Y, C685F,L686V, and G696A in TrkC protein. In some embodiments of any of the kitsdescribed herein, the one or more probes are labeled with a detectableprobe. In some embodiments of any of the kits described herein, the oneor more probes are covalently attached to a substrate (e.g., a film, aplate, or a bead).

As used herein, the word “a” before a noun represents one or more of theparticular noun. For example, the phrase “a cell” represents “one ormore cells.”

The term “subject” means a vertebrate, including any member of the classmammalia, including humans, sports or pet animals, such as horse (e.g.,race horse) or dog (e.g., race dogs), and higher primates. In someembodiments, the subject is a human.

The term “treating” or “positive response to treatment” means animprovement in the condition of a subject having a cancer, e.g., one ormore of a decrease in the size of one or more tumor(s) in a subject, adecrease or no substantial change in the growth rate of one or moretumor(s) in a subject, a decrease in metastasis in a subject, and anincrease in the period of remission for a subject (e.g., as compared tothe one or more metric(s) in a subject having a similar cancer receivingno treatment or a different treatment, or as compared to the one or moremetric(s) in the same subject prior to treatment). Additional metricsfor assessing response to a treatment in a subject having a cancer areknown in the art.

The term “point mutation” means a change in the nucleotide sequence of agene that results in a single amino acid change in a protein encoded bythe gene. For example, a point mutation in a gene can result in thedeletion of a single amino acid in a protein encoded by the gene or canresult in the substitution of an amino acid in a wildtype version of theencoded protein with a different amino acid. Non-limiting examples ofpoint mutations in a NTRK1 genes, NTRK2 genes, and NTRK3 genes aredescribed herein.

The phrase “significant level of carcinogen” is meant a level ofexposure to a carcinogen that is known to increase (e.g., astatistically significant increase) the likelihood of a subject todevelop a cancer (e.g., as compared to a subject that has not beenexposed to the same level of exposure or has been exposed to anon-detectable amount of the carcinogen).

As used herein, a “first Trk kinase inhibitor” or “first Trk inhibitor”is a Trk inhibitor as described herein but does not include compounds ofTable 5, or a pharmaceutically acceptable salt thereof, as definedherein. As used herein, a “second Trk kinase inhibitor” or a “second Trkinhibitor” is a Trk inhibitor as described herein and includes thecompounds of Table 5, or a pharmaceutically acceptable salt thereof, asdescribed herein. When both a first and a second Trk inhibitor arepresent in a method provided herein, the first and second Trk kinaseinhibitors are different.

The term “monotherapy” means the use of a single drug to treat aparticular disorder or disease.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Methods and materials aredescribed herein for use in the present invention; other, suitablemethods and materials known in the art can also be used. The materials,methods, and examples are illustrative only and not intended to belimiting. All publications, patent applications, patents, sequences,database entries, and other references mentioned herein are incorporatedby reference in their entirety. In case of conflict, the presentspecification, including definitions, will control.

Other features and advantages of the invention will be apparent from thefollowing detailed description and figures, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is a flow chart of the experimental methods used in Example 1.

FIG. 2 is a crystal structure of TrkA showing the location of some ofthe Trk inhibitor-resistance amino acid substitutions.

FIG. 3 is a diagram showing the position of some of the Trkinhibitor-resistance amino acid substitutions.

FIG. 4 is a graph of the POC of cells expressing a MPRIP-NTRK1 fusionprotein including one of the Trk inhibitor resistance mutations atdifferent concentrations of(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (Cmpd A).

FIG. 5 is a flow chart of the experimental methods used in Example 3.

FIG. 6A is a graph representing the frequency of mutations and the doseof(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (Cmpd A) from which they were isolated.

FIG. 6B is a schematic of RIP-TRKA (encoded by MPRIP-NTRK1) withselected protein domains and resistance mutations that were identified.

FIG. 6C is a ribbon representation of the crystallographic structure ofthe TRKA kinase domain in complex with the TRK inhibitor AZ-23 (PDB4AOJ) showing localization of mutations that were identified.

FIG. 7 is a graph of the percent of control of cells expressing aMPRIP-NTRK1 fusion protein including certain of the identified TrkAinhibitor resistance mutations at different concentrations of(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (Cmpd A).

FIG. 8 is a photograph of a Western blot analysis of NIH3T3 cellstreated with the indicated concentrations of(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (Cmpd A) for 2 hours.

FIG. 9A is a graph representing the frequency of mutations and the doseof(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (Cmpd A) they were isolated from.

FIG. 9B is a schematic of TRIM24-TRKB (encoded by TRIIM24-NTRK1) withselected protein domains and resistance mutations that were identified.

FIG. 9C is a ribbon representation of the crystallographic structure ofthe TRKB kinase domain in complex with the TRK inhibitor AZ-23 (PDB4AOJ) showing localization of mutations that were identified.

FIG. 10 is a graph of the percent of control of cells expressing aTRIM24-NTRK2 fusion protein including certain of the identified TrkBinhibitor resistance mutations at different concentrations of(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (Cmpd A).

FIG. 11 is a photograph of a Western blot analysis of NIH3T3 cellstreated with the indicated concentrations of(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (Cmpd A) for 2 hours.

FIG. 12 is a table showing the IC₅₀ of certain TrkA and TrkB mutationsthat were identified.

FIG. 13 is an alignment of kinase domains from selected oncogenes withknown resistance mutations. In vitro- (green) or patient-derived(yellow) resistance mutations are shown for other drug-targeted kinasesfor comparison.

DETAILED DESCRIPTION

Trk inhibitor-resistance mutations in a NTRK1 gene, a NTRK2 gene, and aNTRK3 gene were discovered. In view of this discovery, provided hereinare methods of treating a subject having a cancer, methods of selectinga treatment for a subject having a cancer, methods of selecting asubject having a cancer for a treatment that does not include a Trkinhibitor, methods of determining the likelihood that a subject having acancer will have a positive response to a treatment with a Trkinhibitor, methods of predicting the efficacy of a Trk inhibitor in asubject having cancer, methods of determining a subject's risk fordeveloping a Trk inhibitor-resistant cancer, and methods of determiningthe presence of a Trk inhibitor-resistant cancer in a subject, based ona determination as to whether the subject has a cell that has (i) atleast one point mutation in a NTRK1 gene that results in the expressionof a TrkA protein including a mutation at one or more amino acidposition(s) selected from the group consisting of: 517, 542, 568, 573,589, 595, 599, 600, 602, 646, 656, 657, 667, and 676, and/or (ii) atleast one point mutation in a NTRK2 gene that results in the expressionof a TrkB protein including a mutation at one or more amino acidposition(s) selected from the group consisting of: 545, 570, 596, 601,617, 623, 624, 628, 630, 672, 682, 683, 693, and 702, and/or (iii) atleast one point mutation in a NTRK3 gene that results in the expressionof a TrkC protein including a mutation at one or more amino acidposition(s) selected from the group consisting of: 545, 570, 596, 601,617, 623, 624, 628, 630, 675, 685, 686, 696, and 705. Also provided arekits that allow for the detection of at least one of the point mutationsin NTRK1 and/or NTRK2 and/or NTRK3.

Detection and identification of a subject having cells having a Trkinhibitor-resistant mutation as described herein (e.g., (i) at least onepoint mutation in a NTRK1 gene that results in the expression of a TrkAprotein comprising a mutation at one or more amino acid position(s)selected from the group consisting of: 517, 542, 568, 573, 589, 595,599, 600, 602, 646, 656, 657, 667, and 676, and/or (ii) at least onepoint mutation in a NTRK2 gene that results in the expression of a TrkBprotein comprising a mutation at one or more amino acid position(s)selected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 672, 682, 683, 693, and 702, and/or (iii) at least onepoint mutation in a NTRK3 gene that results in the expression of a TrkCprotein comprising a mutation at one or more amino acid position(s)selected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 675, 685, 686, 696, and 705) can improve treatment of thesubject by, for example, changing the treatment regimen (e.g., changingthe Trk inhibitor administered to the subject or adding an additionalanticancer agent or anticancer therapy) or by administering a Trkinhibitor that is effective in the presence of a Trk inhibitor-resistantmutation (e.g., one or more of the compounds of Table 5, or apharmaceutically acceptable salt thereof).

As can be appreciated in the art, the various aspects described belowcan be used in any combination without limitation.

Tropomyosin Receptor Kinases (Trks)

Three different NTRK genes have been implicated as having a role incancer (e.g., through discovery of chromosome translocations resultingin constitutively active Trk fusion proteins): NTRK1, NTRK2, and NTRK3.The NTRK1, NTRK2, and NTRK3 genes encode TrkA, TrkB, and TrkC,respectively.

Non-limiting exemplary amino acid and cDNA sequences for wildtype TrkAare provided below. The exemplary wildtype protein and cDNA sequencesprovided below can be used to identify a point mutation in a NTRK1 geneor can be used to determine mutation in a TrkA protein caused by a pointmutation in a NTRK1 gene, respectively. Additional wildtype protein andcDNA sequences for TrkA are known in the art.

The amino acid positions used to describe the TrkA substitutions hereinare based on the wildtype sequence of TrkA of SEQ ID NO: 1. Thecorresponding amino acid position in the wildtype sequence of anotherisoform of TrkA (SEQ ID NO: 3) can be identified by performing asequence alignment between SEQ ID NO: 1 and SEQ ID NO: 3. A similarmethod (e.g., alignment of SEQ ID NO: 1 to the amino acid sequence ofany other isoform of TrkA) can be used to match the amino acid positionsof the substitutions in TrkA described herein to the corresponding aminoacid position in other isoforms of TrkA known in the art.

Wildtype Human TrkA Protein Isoform A (NP_002520) (SEQ ID NO: 1)

Wildtype Human TrkA cDNA Isoform A (NM_002529) (SEQ ID NO: 2)

Wildtype Human TrkA Protein Isoform B (NP_001007793) (SEQ ID NO: 3)

Wildtype Human TrkA cDNA Isoform B (NM_001007792) (SEQ ID NO: 4)

Alignment of TrkA isoforms (SEQ ID NO: 1 and SEQ ID NO: 3) S1 68LTELYIENQQHLQHLELRDLRGLGELRNLTIVKSGLRFVAPDAFHFTPRLSRLNLSGNAL 127L   YIENQQHLQHLELRDLRGLGELRNLTIVKSGLRFVAPDAFHFTPRLSRLNLSGNAL S3 38LAASYIENQQHLQHLELRDLRGLGELRNLTIVKSGLRFVAPDAFHFTPRLSRLNLSGNAL 97 S1 128ESLSWKTVQGLSLQELVLSGNPLHCSCALRWLQRWEEEGLGGVPEQKLQCHGQGPLAHMP 187ESLSWKTVQGLSLQELVLSGNPLHCSCALRWLQRWEEEGLGGVPEQKLQCHGQGPLAHMP S3 98ESLSWKTVQGLSLQELVLSGNPLHCSCALRWLQRWEEEGLGGVPEQKLQCHGQGPLAHMP 157 S1 188NASCGVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTELEQSATVMKSGGLPSL 247NASCGVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTELEQSATVMKSGGLPSL S3 158NASCGVPTLKVQVPNASVDVGDDVLLRCQVEGRGLEQAGWILTELEQSATVMKSGGLPSL 217 S1 248GLTLANVTSDLNRKNVTCWAENDVGRAEVSVQVNVSFPASVQLHTAVEMHHWCIPFSVDG 307GLTLANVTSDLNRKNVTCWAENDVGRAEVSVQVNVSFPASVQLHTAVEMHHWCIPFSVDG S3 218GLTLANVTSDLNRKNVTCWAENDVGRAEVSVQVNVSFPASVQLHTAVEMHHWCIPFSVDG 277 S1 308QPAPSLRWLFNGSVLNETSFIFTEFLEPAANETVRHGCLRLNQPTHVNNGNYTLLAANPF 367QPAPSLRWLFNGSVLNETSFIFTEFLEPAANETVRHGCLRLNQPTHVNNGNYTLLAANPF S3 278QPAPSLRWLFNGSVLNETSFIFTEFLEPAANETVRHGCLRLNQPTHVNNGNYTLLAANPF 337 S1 368GQASASIMAAFMDNPFEFNPEDPIPVSFSPVDTNSTSGDPVEKKDETPFGVSVAVGLAVF 427GQASASIMAAFMDNPFEFNPEDPIP      DTNSTSGDPVEKKDETPFGVSVAVGLAVF S3 338GQASASIMAAFMDNPFEFNPEDPIP------DTNSTSGDPVEKKDETPFGVSVAVGLAVF 391 S1 428ACLFLSTLLLVLNKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQ 487ACLFLSTLLLVLNKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQ S3 392ACLFLSTLLLVLNKCGRRNKFGINRPAVLAPEDGLAMSLHFMTLGGSSLSPTEGKGSGLQ 451 S1 488GHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKMLVAVKALK 547GHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKMLVAVKALK S3 452GHIIENPQYFSDACVHHIKRRDIVLKWELGEGAFGKVFLAECHNLLPEQDKMLVAVKALK 511 S1 548EASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRFLRSHGPD 607EASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRFLRSHGPD S3 512EASESARQDFQREAELLTMLQHQHIVRFFGVCTEGRPLLMVFEYMRHGDLNRFLRSHGPD 571 S1 608AKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLAGLHFVHRDLATRNCLVGQGLVVKIG 667AKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLAGLHFVHRDLATRNCLVGQGLVVKIG S3 572AKLLAGGEDVAPGPLGLGQLLAVASQVAAGMVYLAGLHFVHRDLATRNCLVGQGLVVKIG 631 S1 668DFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQP 727DFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQP S3 632DFGMSRDIYSTDYYRVGGRTMLPIRWMPPESILYRKFTTESDVWSFGVVLWEIFTYGKQP 691 S1 728WYQLSNTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQALAQA 787WYQLSNTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQALAQA S3 692WYQLSNTEAIDCITQGRELERPRACPPEVYAIMRGCWQREPQQRHSIKDVHARLQALAQA 751 S1 788PPVYLDVLG 796 PPVYLDVLG S3 752 PPVYLDVLG 760

Non-limiting exemplary amino acid and cDNA sequences for wildtype TrkBare provided below. The exemplary wildtype protein and cDNA sequencesprovided below can be used to identify a point mutation in a NTRK2 geneor can be used to determine mutation in a TrkB protein caused by a pointmutation in a NTRK2 gene, respectively. Additional wildtype protein andcDNA sequences for TrkB are known in the art.

The amino acid positions used to describe the TrkB substitutions hereinare based on the wildtype sequence of TrkB of SEQ ID NO: 5. Thecorresponding amino acid position in the wildtype sequence of anotherisoform of TrkB can be identified by performing a sequence alignmentbetween SEQ ID NO: 5 and the amino acid sequence of the other isoform ofTrkB.

Wildtype Human TrkB Protein Isoform A (AAB33109.1) (SEQ ID NO: 5)

Wildtype Human TrkB cDNA Isoform A (S76473.1) (SEQ ID NO: 6)

Non-limiting exemplary amino acid and cDNA sequences for wildtype TrkCare provided below. The exemplary wildtype protein and cDNA sequencesprovided below can be used to identify a point mutation in a NTRK3 geneor can be used to determine mutation in a TrkC protein caused by a pointmutation in a NTRK3 gene, respectively. Additional wildtype protein andcDNA sequences for TrkC are known in the art.

The amino acid positions used to describe the TrkC substitutions hereinare based on the wildtype sequence of TrkC of SEQ ID NO: 7. Thecorresponding amino acid position in the wildtype sequence of anotherisoform of TrkC can be identified by performing a sequence alignmentbetween SEQ ID NO: 7 and the amino acid sequence of the other isoform ofTrkC.

Wildtype Human TrkC Protein (AAB33111.1) (SEQ ID NO: 7)

Wildtype Human TrkC cDNA (S76475.1) (SEQ ID NO: 8)

NTRK Point Mutations

Point mutations in a NTRK1 gene, a NTRK2 gene, and a NTRK3 gene werediscovered in Trk inhibitor-resistant cancer cells. A point mutation ina NTRK1 gene can result in a TrkA protein that includes a substitutionof an amino acid in a wildtype version of the TrkA protein with adifferent amino acid. In other examples, a point mutation in a NTRK1gene can result in a TrkA protein with a deletion of an amino acid in awildtype version of the TrkA protein. Exemplary Trk inhibitor-resistancepoint mutations in TrkA protein are listed in Table 1.

TABLE 1 Exemplary Trk Inhibitor-Resistance Point Mutations in TrkAProtein Amino acid position 517 (e.g., G517R) Amino acid position 542(e.g., A542V) Amino acid position 568 (e.g., Q568x) Amino acid position573 (e.g., V573M) Amino acid position 589 (e.g., F589L, F589C) Aminoacid position 595 (e.g., G595S, G595R¹) Amino acid position 599 (e.g.,D596V) Amino acid position 600 (e.g., F600L) Amino acid position 602(e.g., R602x) Amino acid position 646 (e.g., F646V) Amino acid position656 (e.g., C656Y, C656F) Amino acid position 657 (e.g., L657V) Aminoacid position 667 (e.g., G667C¹, G667S) Amino acid position 676 (e.g.,Y676S)The letter “x” when used to describe a mutation of an amino acid at aspecific amino acid position means (i) a substitution of the amino acidpresent at the same amino acid position in the corresponding wildtypeprotein with a different naturally-occurring amino acid, or (ii) adeletion of the amino acid present at the same amino acid position inthe corresponding wildtype protein.

A point mutation in a NTRK2 gene can result in a TrkB protein thatincludes a substitution of an amino acid in a wildtype version of theTrkB protein with a different amino acid. In other examples, a pointmutation in a NTRK2 gene can result in a TrkB protein with a deletion ofan amino acid in a wildtype version of the TrkB protein. Exemplary Trkinhibitor-resistance point mutations in TrkB protein are listed in Table2.

TABLE 2 Exemplary Trk Inhibitor-Resistance Point Mutations in TrkBProtein Amino acid position 545 (e.g., G545R) Amino acid position 570(e.g., A570V) Amino acid position 596 (e.g., Q596E, Q596P) Amino acidposition 601 (e.g., V601G) Amino acid position 617 (e.g., F617L, F617C,F617I) Amino acid position 623 (e.g., G623S, G623R) Amino acid position624 (e.g., D624V) Amino acid position 628 (e.g., F628x) Amino acidposition 630 (e.g., R630K) Amino acid position 672 (e.g., F672x) Aminoacid position 682 (e.g., C682Y, C682F) Amino acid position 683 (e.g.,L683V) Amino acid position 693 (e.g., G693S) Amino acid position 702(e.g., Y702x)The letter “x” when used to describe a mutation of an amino acid at aspecific amino acid position means (i) a substitution of the amino acidpresent at the same amino acid position in the corresponding wildtypeprotein with a different naturally-occurring amino acid, or (ii) adeletion of the amino acid present at the same amino acid position inthe corresponding wildtype protein.

A point mutation in a NTRK3 gene can result in a TrkC protein thatincludes a substitution of an amino acid in a wildtype version of theTrkC protein with a different amino acid. In other examples, a pointmutation in a NTRK3 gene can result in a TrkC protein with a deletion ofan amino acid in a wildtype version of the TrkC protein. Exemplary Trkinhibitor-resistance NTRK3 mutations are listed in Table 3.

TABLE 3 Exemplary Trk Inhibitor-Resistance Point Mutations in TrkCProtein Amino acid position 545 (e.g., G545R) Amino acid position 570(e.g., A570V) Amino acid position 596 (e.g., Q596x) Amino acid position601 (e.g., V601) Amino acid position 617 (e.g., F617x) F617L Amino acidposition 623 (e.g., G623R¹) Amino acid position 624 (e.g., D624V) Aminoacid position 628 (e.g., F628x) Amino acid position 630 (e.g., R630x)Amino acid position 675 (e.g., F675x) Amino acid position 685 (e.g.,C685Y, C684F) Amino acid position 686 (e.g., L686V) Amino acid position696 (e.g., G696x) G696A Amino acid position 705 (e.g., Y705x)The letter “x” when used to describe a mutation of an amino acid at aspecific amino acid position means (i) a substitution of the amino acidpresent at the same amino acid position in the corresponding wildtypeprotein with a different naturally-occurring amino acid, or (ii) adeletion of the amino acid present at the same amino acid position inthe corresponding wildtype protein.

Non-limiting examples of the specific amino acid positions discovered tohave mutations (e.g., substitutions or deletions) in TrkA in Trkinhibitor-resistant cancer cells having a NTRK1 point mutation arelisted below. Also listed below are the different specific amino acidmutations (e.g., substitutions) present in TrkA proteins present in Trkinhibitor-resistant cancer cells having a NTRK1 point mutation.

Trk inhibitor-resistant cancer cells were discovered to have pointmutations in a NTRK1 gene that result in a TrkA protein that includesone or more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid substitutionsor deletions at amino acid positions: 517, 542, 568, 573, 589, 595, 599,600, 602, 646, 656, 657, 667, and 676 (e.g., amino acid positionscorresponding to those in wildtype sequence NP_002520 (SEQ ID NO: 1)).Different specific amino acid substitutions present in a TrkA proteingenerated in a Trk inhibitor-resistant cancer cell include one or more(e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, ortwelve) of the following: G517R, A542V, V573M, F589L, F589C, G595S,G595R, D596V, F600L, F646V, C656Y, C656F, L657V, G667S, G667C, and Y676S(e.g., as compared to the wildtype sequence NP_002520 (SEQ ID NO: 1)).

Trk inhibitor-resistant cancer cells were discovered to have pointmutations in a NTRK2 gene that result in a TrkB protein that includesone or more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid substitutionsor deletions at amino acid positions: 545, 570, 596, 601, 617, 623, 624,628, 630, 672, 682, 683, 693, and 702 (e.g., amino acid positionscorresponding to those in wildtype sequence AAB33109.1 (SEQ ID NO: 5)).Different specific amino acid substitutions present in a TrkB proteingenerated in a Trk inhibitor-resistant cancer cell include one or more(e.g., two, three, four, five, six, seven, eight, nine, eleven, ortwelve) of the following: G545R, A570V, Q596E, Q596P, V601G, F617L,F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S,and G713S (e.g., as compared to the wildtype sequence AAB33109.1 (SEQ IDNO: 5)).

Trk inhibitor-resistant cancer cells were discovered to have pointmutations in a NTRK3 gene that result in a TrkC protein that includesone or more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid substitutionsor deletions at amino acid positions: 545, 570, 596, 601, 617, 623, 624,628, 630, 675, 685, 686, 696, and 705 (e.g., amino acid positionscorresponding to those in a wildtype sequence (SEQ ID NO: 7)). Differentspecific amino acid substitutions present in a TrkC protein generated ina Trk inhibitor-resistant cancer cell include one or more (e.g., two,three, four, five, six, or seven, or eight) of the following: G545R,A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A (e.g., ascompared to the wildtype sequence (SEQ ID NO: 7)).

As one skilled in the art can appreciate, the specific substitutionslisted above are exemplary. For example, when a naturally-occurringamino acid at an amino acid position is substituted with a differentamino acid, it is understood that an amino acid having achemically-related amino acid side chain may also be substituted (anddetected in a cancer cell). Amino acids that have chemically-relatedamino acid side chains are listed in Table 4.

TABLE 4 Chemically Related Amino Acid Side Chains Positively-ChargedLysine, Arginine, Histidine Side Chains Negatively-Charged Glutamate andAspartate Side Chains Nonpolar and/or Glycine, Alanine, Valine, Leucine,Isoleucine, Aliphatic Side Groups and Proline Polar, Uncharged SideSerine, Threonine, Cysteine, Methionine, Groups Asparagine, GlutamineAromatic Side Chains Phenylalanine, Tyrosine, and Tryptophan

Any of the point mutations described herein may result in, e.g.,increased catalytic activity of a TrkA kinase or a TrkB kinase or a TrkCkinase. Any of the point mutations described herein may result in, e.g.,a decrease in the auto-inhibited conformation of a Trk kinase (e.g., aTrkA kinase or a TrkB kinase or a TrkC kinase). Any of the pointmutations described herein may result in, e.g., an increase in theactivated conformation of a Trk kinase (e.g., a TrkA kinase or a TrkBkinase or a TrkC kinase). Any of the point mutations described hereinmay result in, e.g., an altered tertiary structure of a TrkA kinase (ascompared to a wildtype TrkA kinase) that decreases binding of a Trkinhibitor to the TrkA kinase, or an altered tertiary structure of a TrkBkinase (as compared to a wildtype TrkB kinase) that decreases binding ofa Trk inhibitor to the TrkB kinase, or an altered tertiary structure ofa TrkC kinase (as compared to a wildtype TrkC kinase) that decreasesbinding of a Trk inhibitor to the TrkC kinase. Any of the pointmutations described herein may result in, e.g., an increase in theK_(off) rate and/or a decrease in the K_(on) rate of a Trk inhibitorwhen it interacts with the TrkA protein (as compared to a wildtype TrkAkinase) or the TrkB protein (as compared to a wildtype TrkB kinase) orthe TrkC protein (as compared to a wildtype TrkC kinase).

Isolating Genomic DNA from a Biopsy Sample

Methods of isolating genomic DNA from biopsy sample are well known inthe art. For example, a number of commercially available kits can beused to isolate genomic DNA from a sample containing mammalian cells(e.g., a biopsy sample). Non-limiting examples of commercially availablekits for the isolation of genomic DNA from a sample containing mammaliancells include: ChargeSwitch® gDNA Tissue Kit (Life Technologies),Genomic DNA Isolation Kit (Norgen Biotek Corp., Ontario, Canada), QIAmpDNA FFPE (Qiagen), QIAsymphony DSP DNA kits (Qiagen), REPLI-g Mini Kit(Qiagen), Generation Capture Plate Kit (Qiagen), QI Amp 96 DNA Blood Kit(Qiagen), QIAmp DNA Mini kit (Qiagen), Biosprint 15 DNA Bloot Kit(Qiagen), Biosprint 96 DNA Blood Kit (Qiagen), MagAttract DNA Mini M48Kit (Qiagen), QIAmp DNA Blood BioRobot 9604 Kit (Qiagen), QIAmp DNAInvestigator Kit (Qiagen), QIAmp DNA Micro Kit, Xtreme DNA Isolation Kit(Isohelix; Harrietsham, Kent, UK), DDK DNA Isolation Kit (Isohelix), andXtraClean DNA kit (Isohelix). Genomic DNA can be isolated from a sample(e.g., a biopsy sample) using these and other commercially availablegenomic DNA isolation kits by following the manufacturer's instructions.

An exemplary method for isolating genomic DNA from a sample (e.g., abiopsy sample) include the steps of: lysing mammalian cells present inthe sample, precipitating proteins in the lysate, removing thesupernatant, precipitating genomic DNA out of the supernatant, washingthe genomic DNA pellet with ethanol, and rehydrating the genomic DNApellet in a pharmaceutically acceptable buffer (e.g., sterile orfiltered water, or a buffered solution).

Assays for Determining the Presence of a Point Mutation

Some of the methods provided herein include a step of performing anassay to determine the presence of (i) at least one (e.g., two, three,four, five, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) point mutation in a NTRK1 gene (e.g.,any of the point mutations in NTRK1 described herein), and/or (ii) atleast one (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK2 gene, and/or (iii) at least one (e.g., two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, orfifteen) point mutation in a NTRK3 gene (e.g., any of the pointmutations in a NTRK3 gene described herein), in a cell (e.g., cancercell) in a sample from the subject (e.g., a biopsy sample).

A variety of assays for determining the presence of one or more pointmutations in a cell (e.g., a cancer cell) are known in the art.Non-limiting examples of such assays (which can be used in any of themethods described herein) include: denaturing gradient gelelectrophoresis (DGGE) (Nollau et al., Clin. Chem. 43:1114-1128, 1997),temperature gradient gel electrophoresis (TGGE) (Nollau et al., Clin.Chem. 43:1114-1128, 1997), temperature gradient capillaryelectrophoresis, single strand conformational polymorphism assays (see,e.g., Tahira et al., Human Mutat. 26:69-77, 2005), molecular beaconassays (see, e.g., Totowa, N.J., Vol. 212, pp. 111-128, 2003), dynamichybridization (see, e.g., Howell et al., Nature Biotechnol. 17:87-88,1999), PCR-based assays (e.g., tetraprimer ARMS-PCR (see, e.g., Zhang etal., Plos One 8:e62126, 2013), real-time PCR, allele-specific PCR (see,e.g., Gaudet et al., Methods Mol. Biol. 578:415-424, 2009), and TaqManAssay Genotyping (see, e.g., Woodward, Methods Mol. Biol. 1145:67-74,2014, and TaqMan®OpenArray® Genotyping Plates from Life Technologies)),Flap endonuclease assays (also called Invader assays) (see, e.g.,Olivier et al., Mutat. Res. 573:103-110, 2005), oligonucleotide ligationassays (see, e.g., Bruse et al., Biotechniques 45:559-571, 2008), or,denaturing high performance liquid chromatography (see, e.g., Yu et al.,J Clin. Pathol. 58:479-485, 2005), high-resolution melting of anamplified sequence containing the point mutation (see, e.g., Wittwer etal., Clinical Chemistry 49:853-860, 2003), or sequencing (e.g.,Maxam-Gilbert sequencing, chain-termination methods, shotgun sequencing,bridge PCR, and next-generation sequencing methods (e.g., massivelyparallel signature sequencing, polony sequencing, 454 pyrosequencing,Illumina (Solexa) sequencing, SOLiD sequencing, Ion Torrentsemiconductor sequence, DNA nanoball sequencing, heliscope singlemolecule sequencing, and single molecule real-time sequencing)).Additional details and a summary of various next-generation sequencingmethods are described in Koboldt et al., Cell 155:27-38, 2013.

In some embodiments, the assay used to determine the presence of the (i)at least one point mutation in NTRK1, and/or (ii) at least one pointmutation in NTRK2, and/or (iii) at least one point mutation in a NTRK3,includes a PCR assay (e.g., a real-time PCR-assay, e.g., a real-timePCR-based genotyping assay) (with or without a prior pre-amplificationstep). In some embodiments of any of the methods described herein theassay used to determine the presence of (i) at least one point mutationin NTRK1, and/or (ii) at least one point mutation in NTRK2, and/or (iii)at least one point mutation in NTRK3, is performed using TaqMan®-basedsequencing (e.g., TaqMan®-based OpenArray® sequencing, e.g., highthroughput TaqMan®-based Open Array® sequencing) (with or without aprior pre-amplification step). Methods for designing primers for use inthe assays described herein are well-known in the art. For example,several vendors provide free software for designing forward and reverseprimers for use in any of the assays described herein. A forward orreverse primer for use in any of the assays described herein can containat least 10 (e.g., 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23,24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41,42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleotides). In some examples, aforward or reverse primer used in any of the assays described herein caninclude a label (e.g., any of the exemplary labels described herein) orcan include a contiguous tag sequence (e.g., between about 5 nucleotidesand about 25 nucleotides, between about 10 nucleotides and about 25nucleotides, between about 10 nucleotides and 20 nucleotides, betweenabout 5 nucleotides and about 20 nucleotides) that does not hybridize toa sequence within the subject's genome (e.g., the human genome).

In some embodiments, the assay includes the use of: one or more probes(e.g., detectably labeled probes) that specifically hybridize to one ormore segments of a NTRK1 gene that include a point mutation (e.g., anyof the point mutations in NTRK1 described herein); and/or one or moreprobes (e.g., detectable labeled probes) that specifically hybridize toone or more segments of a NTRK2 gene that include a point mutation(e.g., any of the point mutations in NTRK2 described herein); and/or oneor more probes (e.g., a detectable labeled probe) that specificallyhybridizes to one or more segments of a NTRK3 gene that include a pointmutation (e.g., any of the point mutations in NTRK3 described herein).For example, the one or more probes can have 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,34, or 35 nucleotides. Additional description of the probes that can beused in exemplary assays are described herein.

Subjects

In various embodiments of the methods described herein, the subject canbe previously identified or diagnosed as having a cancer (e.g., any ofthe cancers described herein). A subject can, e.g., be previouslyidentified as having a cancer cell that has at least one point mutationin a NTRK gene that results in the expression of a Trk protein includinga mutation at one or more amino acid positions. For example, (i) atleast one (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK1 gene (e.g., any of the NTRK1 point mutations described herein),and/or (ii) at least one (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) pointmutation in a NTRK2 gene (e.g., any of the NTRK2 point mutationsdescribed herein), and/or (iii) at least one (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) point mutation in a NTRK3 gene (e.g., any of the NTRK3 pointmutations described herein). In some embodiments, a subject can bepreviously identified as having (i) at least one (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK1 gene that results in theexpression of a TrkA protein including a mutation (e.g., substitution)at one or more (e.g., two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or fifteen) amino acidposition(s) selected from the group consisting of: 517, 542, 568, 573,589, 595, 599, 600, 602, 646, 656, 657, 667, and 676 (e.g., a TrkAprotein including one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, or twelve) of G517R, A542V, V573M, F589L,F589C, G595S, G595R, D596V, F600L, F646V, C656Y, C656F, L657V, G667S,G667C, and Y676S); and/or (ii) at least one (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) point mutation in a NTRK2 gene that results in theexpression of a TrkB including a mutation (e.g., substitution) at one ormore (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid position(s)selected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 672, 682, 683, 693, and 702 (e.g., a TrkB proteinincluding one or more (e.g., two, three, four, five, six, seven, eight,nine, ten, eleven, or twelve) of G545R, A570V, Q596E, Q596P, V601G,F617L, F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F, L683V,G693S, and G713S; and/or (iii) at least one (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) point mutation in a NTRK3 gene that results in theexpression of a TrkC protein comprising a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid position(s) selected from thegroup consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675,685, 686, 696, and 705 (e.g., a TrkC protein including one or more(e.g., two, three, four, five, six, seven, or eight) of G545R, A570V,F617L, G623R, D624V, C685Y, C685F, L686V, and G696A).

In the methods of determining a subject's risk of developing a Trkinhibitor-resistant cancer and the methods of determining the presenceof a Trk inhibitor-resistant cancer in a subject, the subject can be anundiagnosed subject, the subject can be identified as having beenexposed to a significant level of carcinogen(s), the subject can besuspected of having a cancer (e.g., any of the cancers describedherein), the subject can present with one or more (e.g., two, three,four, or five) symptoms of cancer (e.g., any of the symptoms of cancerdescribed herein), and/or the subject is known to an elevated risk ofdeveloping a cancer (e.g., a family history of cancer).

In some embodiments, the subject is a pediatric subject.

The term “pediatric subject” as used herein refers to a patient underthe age of 21 years at the time of diagnosis or treatment. The term“pediatric” can be further be divided into various subpopulationsincluding: neonates (from birth through the first month of life);infants (1 month up to two years of age); children (two years of age upto 12 years of age); and adolescents (12 years of age through 21 yearsof age (up to, but not including, the twenty-second birthday)). BerhmanR E, Kliegman R, Arvin A M, Nelson W E. Nelson Textbook of Pediatrics,15th Ed. Philadelphia: W.B. Saunders Company, 1996; Rudolph A M, et al.Rudolph's Pediatrics, 21st Ed. New York: McGraw-Hill, 2002; and Avery MD, First L R. Pediatric Medicine, 2nd Ed. Baltimore: Williams & Wilkins;1994. In some embodiments, a pediatric subject is from birth through thefirst 28 days of life, from 29 days of age to less than two years ofage, from two years of age to less than 12 years of age, or 12 years ofage through 21 years of age (up to, but not including, the twenty-secondbirthday). In some embodiments, a pediatric subject is from birththrough the first 28 days of life, from 29 days of age to less than 1year of age, from one month of age to less than four months of age, fromthree months of age to less than seven months of age, from six months ofage to less than 1 year of age, from 1 year of age to less than 2 yearsof age, from 2 years of age to less than 3 years of age, from 2 years ofage to less than seven years of age, from 3 years of age to less than 5years of age, from 5 years of age to less than 10 years of age, from 6years of age to less than 13 years of age, from 10 years of age to lessthan 15 years of age, or from 15 years of age to less than 22 years ofage.

Cancers

Methods of treating a cancer are provided herein. Point mutations inNTRK1, NTRK2, and NTRK3 were found in Trk inhibitor-resistant cancercells. Non-limiting examples of cancer (e.g., a Trk-associated cancer)include adenocarcinoma, adrenal gland cortical carcinoma, adrenal glandneuroblastoma, anus squamous cell carcinoma, appendix adenocarcinoma,bladder urothelial carcinoma, bile duct adenocarcinoma, bladdercarcinoma, bladder urothelial carcinoma, bone chordoma, bone marrowleukemia lymphocytic chronic, bone marrow leukemia non-lymphocytic acutemyelocytic, bone marrow lymph proliferative disease, bone marrowmultiple myeloma, bone sarcoma, brain astrocytoma, brain glioblastoma,brain medulloblastoma, brain meningioma, brain oligodendroglioma, breastadenoid cystic carcinoma, breast carcinoma, breast ductal carcinoma insitu, breast invasive ductal carcinoma, breast invasive lobularcarcinoma, breast metaplastic carcinoma, cervix neuroendocrinecarcinoma, cervix squamous cell carcinoma, colon adenocarcinoma, coloncarcinoid tumor, duodenum adenocarcinoma, endometrioid tumor, esophagusadenocarcinoma, eye intraocular melanoma, eye intraocular squamous cellcarcinoma, eye lacrimal duct carcinoma, fallopian tube serous carcinoma,gallbladder adenocarcinoma, gallbladder glomus tumor, gastroesophagealjunction adenocarcinoma, head and neck adenoid cystic carcinoma, headand neck carcinoma, head and neck neuroblastoma, head and neck squamouscell carcinoma, kidney chromophore carcinoma, kidney medullarycarcinoma, kidney renal cell carcinoma, kidney renal papillarycarcinoma, kidney sarcomatoid carcinoma, kidney urothelial carcinoma,leukemia lymphocytic, liver cholangiocarcinoma, liver hepatocellularcarcinoma, lung adenocarcinoma, lung adenosquamous carcinoma, lungatypical carcinoid, lung carcinosarcoma, lung large cell neuroendocrinecarcinoma, lung non-small cell lung carcinoma, lung sarcoma, lungsarcomatoid carcinoma, lung small cell carcinoma, lung small cellundifferentiated carcinoma, lung squamous cell carcinoma, lymph nodelymphoma diffuse large B cell, lymph node lymphoma follicular lymphoma,lymph node lymphoma mediastinal B-cell, lymph node lymphomaplasmablastic lung adenocarcinoma, lymphoma follicular lymphoma,lymphoma, non-Hodgkin's lymphoma, nasopharynx and paranasal sinusesundifferentiated carcinoma, ovary carcinoma, ovary carcinosarcoma, ovaryclear cell carcinoma, ovary epithelial carcinoma, ovary granulosa celltumor, ovary serous carcinoma, pancreas carcinoma, pancreas ductaladenocarcinoma, pancreas neuroendocrine carcinoma, peritoneummesothelioma, peritoneum serous carcinoma, placenta choriocarcinoma,pleura mesothelioma, prostate acinar adenocarcinoma, prostate carcinoma,rectum adenocarcinoma, rectum squamous cell carcinoma, skin adnexalcarcinoma, skin basal cell carcinoma, skin melanoma, skin Merkel cellcarcinoma, skin squamous cell carcinoma, small intestine adenocarcinoma,small intestine gastrointestinal stromal tumors (GISTs), soft tissueangiosarcoma, soft tissue Ewing sarcoma, soft tissuehemangioendothelioma, soft tissue inflammatory myofibroblastic tumor,soft tissue leiomyosarcoma, soft tissue liposarcoma, soft tissueneuroblastoma, soft tissue paraganglioma, soft tissue perivascularepitheliod cell tumor, soft tissue sarcoma, soft tissue synovialsarcoma, stomach adenocarcinoma, stomach adenocarcinoma diffuse-type,stomach adenocarcinoma intestinal type, stomach adenocarcinomaintestinal type, stomach leiomyosarcoma, thymus carcinoma, thymusthymoma lymphocytic, thyroid papillary carcinoma, unknown primaryadenocarcinoma, unknown primary carcinoma, unknown primary malignantneoplasm, unknown primary melanoma, unknown primary sarcomatoidcarcinoma, unknown primary squamous cell carcinoma, unknownundifferentiated neuroendocrine carcinoma, unknown primaryundifferentiated small cell carcinoma, uterus carcinosarcoma, uterusendometrial adenocarcinoma, uterus endometrial adenocarcinomaendometrioid, uterus endometrial adenocarcinoma papillary serous, anduterus leiomyosarcoma.

Additional examples of cancers (e.g., Trk inhibitor-resistant cancer)include: adrenocortical carcinoma, anal cancer, appendix cancer,atypical teratoid/rhabdoid tumor (e.g., central nervous system atypicalteratoid/rhabdoid tumor), B-cell cancer, bile duct cancer, bladdercancer, bone cancer (e.g., osteosarcoma and malignant fibroushistiocytoma), brain cancer (e.g., brain and spinal cord tumor, brainstem glioma, central nervous system embryonal tumors, central nervoussystem germ cell tumors, craniopharyngioma, and ependymoma), breastcancer, bronchogenic carcinoma, bronchus cancer, cancer of hematologicaltissues, cancer of the oral cavity or pharynx, carcinoid tumor, cervicalcancer, childhood cancers, chordoma, chronic lymphocytic leukemia,chronic myeloproliferative neoplasms, colon cancer, colorectal cancer,cutaneous T-cell lymphoma, ductal carcinoma in situ, embryonal tumor,endometrial cancer, esophageal cancer, esthesioneuroblastoma,extracranial germ cell tumor, extragonadal germ cell tumor, extrahepaticbile duct cancer, eye cancer (e.g., retinoblastoma), fallopian tubecancer, fibrosarcoma, fibrous histiocytoma of bone, gallbladder cancer,gastric cancer, gastrointestinal carcinoid tumor, germ cell tumor,gestational trophoblastic disease, glioblastoma multiforme, glioma(e.g., lower-grade glioma), head and neck cancer, heart cancer,histiocytosis, hypopharyngeal cancer, inflammatory myofibroblastictumors, intrahepatic cholangiocarcinoma, islet cell tumor, kidney cancer(e.g., renal cell cancer), Langerhans cell histiocytosis, large cellneuroendocrine cancer, laryngeal cancer, leukemia (e.g., acutelymphoblastic leukemia, acute myeloid leukemia, chronic myelogenousleukemia, and hairy cell leukemia), lip cancer, liver cancer, lungcancer, Burkitt lymphoma, Hodgkin's lymphoma, and primary centralnervous system lymphoma), medulloblastoma, mesothelioma, mouth cancer,multiple myeloma, myelodysplastic syndromes, nasal cavity and paranasalsinus cancer, nasopharyngeal cancer, neoplasm (e.g., a melanocysticneoplasm), nephroma, neuroblastoma, non-small cell lung cancer, oralcancer, oropharyngeal cancer, ovarian cancer, pancreatic cancer,paraganglioma, parathyroid cancer, pediatric glioma, penile cancer,pharyngeal cancer, pheochromocytoma, pilocytic astrocytoma, pituitarytumor, plasma cell neoplasm, primary peritoneal cancer, prostate cancer,rectum carcinoma, salivary gland cancer, sarcoma (e.g., Ewing sarcoma,rhabdomyosarcoma, uterine sarcoma, and undifferentiated sarcoma),secretory breast carcinoma, Sezary syndrome, skin cancer, small bowelcancer, small cell lung cancer, small intestine cancer, Spitz nevi,Spitz tumors, spitzoid melanoma, stomach cancer, squamous cellcarcinoma, squamous neck cancer, testicular cancer, throat cancer,thymoma and thymic carcinoma, thyroid carcinoma, urethral cancer,uterine cancer, urinary bladder cancer, vaginal cancer, vulvar cancer,and Wilms tumor.

In some embodiments, the cancer is a pediatric cancer. In someembodiments, the pediatric cancer is a mesenchymal cancer. For example,the mesenchymal cancer can be selected from the group consisting of:pediatric nephroma, congenital fibrosarcoma (CFS), pediatric high-gradeglioma (HGG), mesenchymal cancers (infant fibrosarcoma (IF), congenitalmesoblastic nephroma, congenital infantile fibrosarcoma (CIFS);pilocytic astrocytoma, brain tumors, pediatic acute leukemia, Ph-likeacute lymphoblastic leukemia, cellular congenital mesoblastic nephroma(CMN); infantile fibrosarcoma, pediatric high-grade glioma (HGG),diffuse intrinsic pontine gliomas (DIPGs), non-brainstem HGGs(NBS-HGGs), anaplastic large cell lymphoma (ALCL), non-Hodgkin'slymphoma (NHL), pediatric papillary thyroid carcinoma, soft tissuesarcoma, spitzoid melanoma, pediatric hemangiopericytoma-like sarcoma,spindle cell sarcoma, NOS with myo/haemangiopericytic growth pattern,lung cancer, advanced pediatric solid tumors, neuroectodermal-derivedtumors, pediatric colorectal cancer, adrenal neuroblastoma, and centralnervous system tumors.

In some embodiments, the pediatric cancer is a fibrosarcoma such asinfantile fibrosarcoma.

In some embodiments, the pediatric cancer is a glioma. For example, thepediatric cancer is selected from the group consisting of: pediatrichigh-grade glioma (HGG), diffuse intrinsic pontine gliomas (DIPGs), andon-brainstem HGGs (NBS-HGGs).

Methods of diagnosing a cancer (e.g., any of the cancers describedherein) are known in the art. For example, a health care professional(e.g., a physician) can diagnose a subject as having a cancer byobserving one or more symptoms of a cancer in the subject. Non-limitingexamples of symptoms of a cancer include fever, fatigue, pain,hyperpigmentation, jaundice, erythema, pruritis, excessive hair growth,long-term constipation, diarrhea, change in the size of stool, pain whenurinating, blood in urine, change in bladder function, sore that do notheal, white patches inside the mouth or on tongue, unusual bleeding ordischarge, indigestion, trouble swallowing, changes in warts, moles, orfreckles, nagging cough, hoarseness, lump or area of thickening that canbe felt under skin, weight changes, trouble breathing, discomfort aftereating, persistent, unexplained muscle or joint pain, persistent,unexplained fevers and night sweats, and unexplained bruising. Thediagnosis of a cancer by a health care profession (e.g., a physician)can also include performing laboratory tests (e.g., urine or bloodtests, e.g., complete blood count), imaging tests (e.g., computerizedtomography (CT), bone scan, magnetic resonance imaging (MRI), positronemission tomography (PET) scan, ultrasound, and X-ray), and obtainingand/or examining a biopsy sample from the subject.

A Trk inhibitor-resistant cancer cell can have, e.g., an increased rateof growth in the presence of at least one Trk inhibitor (e.g., any ofthe Trk inhibitors described herein or known in the art) as compared tothe rate of growth of a control cell from a control subject having thesame type of cancer and not having one or more of the point mutations ina NTRK1 gene described herein or one or more of the point mutations in aNTRK2 gene described herein or a point mutation in a NTRK3 genedescribed herein, when it is contacted with the at least one Trkinhibitor (e.g., a first Trk inhibitor). One of skill in the art willappreciate that the Trk inhibitor-resistant cancer cell and the controlcell are contacted with the same concentration of the at least one Trkinhibitor. For example, rate of growth of the Trk inhibitor-resistantcancer cell is increased about 1% to about 100%, about 95%, about 90%,about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 25%,about 20%, about 15, about 10%, or about 5%; about 5% to about 100%,about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%,about 30%, about 25%, about 20%, about 15, or about 10%; about 10% toabout 100%, about 95%, about 90%, about 85%, about 80%, about 75%, about70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%,about 35%, about 30%, about 25%, about 20%, or about 15%; about 15% toabout 100%, about 95%, about 90%, about 85%, about 80%, about 75%, about70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%,about 35%, about 30%, about 25%, or about 20%; about 20% to about 100%,about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%,about 30%, or about 25%; about 25% to about 100%, about 95%, about 90%,about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about55%, about 50%, about 45%, about 40%, about 35%, or about 30%; about 30%to about 100%, about 95%, about 90%, about 85%, about 80%, about 75%,about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about40%, or about 35%; about 35% to about 100%, about 95%, about 90%, about85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%,about 50%, about 45%, or about 40%; about 40% to about 100%, about 95%,about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about60%, about 55%, about 50%, or about 45%; about 45% to about 100%, about95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%,about 60%, about 55%, to about 50%; about 50% to about 100%, about 95%,about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about60%, to about 55%; about 55% to about 100%, about 95%, about 90%, about85%, about 80%, about 75%, about 70%, about 65%, or about 60%; about 60%to about 100%, about 95%, about 90%, about 85%, about 80%, about 75%,about 70%, or about 65%; about 65% to about 100%, about 95%, about 90%,about 85%, about 80%, about 75%, or about 70%; about 70% to about 100%,about 95%, about 90%, about 85%, about 80%, to about 75%; about 75% toabout 100%, about 95%, about 90%, about 85%, or about 80%; about 80% toabout 100%, about 95%, about 90%, or about 85%; about 85% to about 100%,about 95%, or about 90%; about 90% to about 100% or about 95%; or about95% to about 100% (as compared to the rate of growth of a control cellfrom a control subject having the same type of cancer and not having oneor more of the point mutations in a NTRK1 gene described herein or oneor more of the point mutations in a NTRK2 gene described herein or oneor more of the point mutations in a NTRK3 gene described herein, when itis contacted with the at least one Trk inhibitor).

In some embodiments, a Trk inhibitor-resistant cancer can be resistantto treatment with(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (or a polymorph thereof), but the Trk inhibitor-resistant canceris still sensitive to a treatment including one or more compounds ofTable 5, or a pharmaceutically acceptable salt thereof. In someembodiments, a Trk inhibitor-resistant cancer can be resistant totreatment with entrectinib, but the Trk inhibitor-resistant cancer isstill sensitive to a treatment including one or more compounds of Table5, or a pharmaceutically acceptable salt thereof.

A Trk inhibitor-resistant cancer in a subject can have, e.g., anincreased rate of growth of a solid tumor when the subject is treatedwith at least one Trk inhibitor (e.g., a first Trk inhibitor) ascompared to the rate of growth of a control solid tumor in a controlsubject treated with the at least one Trk inhibitor and having the sametype of cancer and not having one or more of the point mutations in aNTRK1 gene described herein or one or more of the point mutations in aNTRK2 gene described herein or a point mutation in a NTRK3 genedescribed herein). One of skill in the art will appreciate that thesubject and the control subject are administered the same concentrationof the at least one Trk inhibitor. For example, rate of growth of thesolid tumor in a subject having a Trk inhibitor-resistant cancer andadministered at least one Trk inhibitor is increased about 1% to about100%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%,about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about35%, about 30%, about 25%, about 20%, about 15, about 10%, or about 5%;about 5% to about 100%, about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15, orabout 10%; about 10% to about 100%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%,or about 15%; about 15% to about 100%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about50%, about 45%, about 40%, about 35%, about 30%, about 25%, or about20%; about 20% to about 100%, about 95%, about 90%, about 85%, about80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%,about 45%, about 40%, about 35%, about 30%, or about 25%; about 25% toabout 100%, about 95%, about 90%, about 85%, about 80%, about 75%, about70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%,about 35%, or about 30%; about 30% to about 100%, about 95%, about 90%,about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about55%, about 50%, about 45%, about 40%, or about 35%; about 35% to about100%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%,about 65%, about 60%, about 55%, about 50%, about 45%, or about 40%;about 40% to about 100%, about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, orabout 45%; about 45% to about 100%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, toabout 50%; about 50% to about 100%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, to about 55%;about 55% to about 100%, about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 65%, or about 60%; about 60% to about 100%,about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, orabout 65%; about 65% to about 100%, about 95%, about 90%, about 85%,about 80%, about 75%, or about 70%; about 70% to about 100%, about 95%,about 90%, about 85%, about 80%, to about 75%; about 75% to about 100%,about 95%, about 90%, about 85%, or about 80%; about 80% to about 100%,about 95%, about 90%, or about 85%; about 85% to about 100%, about 95%,or about 90%; about 90% to about 100% or about 95%; or about 95% toabout 100% (as compared to the rate of growth of a solid tumor in acontrol subject having the same type of cancer and not having one ormore of the point mutations in a NTRK1 gene described herein or one ormore of the point mutations in a NTRK2 gene described herein or a pointmutation in a NTRK3 gene described herein, and administered the same atleast one Trk inhibitor).

A Trk inhibitor-resistant cancer in a subject can have, e.g., adecreased rate of apoptosis in a solid tumor when the subject is treatedwith at least one Trk inhibitor (e.g., a first Trk inhibitor) ascompared to the rate of apoptosis of a control solid tumor in a controlsubject treated with the at least one Trk inhibitor and having the sametype of cancer and not having one or more of the point mutations in aNTRK1 gene described herein or one or more of the point mutations in aNTRK2 gene described herein or one or more point mutations in a NTRK3gene described herein). One of skill in the art will appreciate that thesubject and the control subject are administered the same concentrationof the at least one Trk inhibitor. For example, rate of apoptosis of thesolid tumor in a subject having a Trk inhibitor-resistant cancer andadministered at least one Trk inhibitor is decreased about 1% to about100%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%,about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about35%, about 30%, about 25%, about 20%, about 15, about 10%, or about 5%;about 5% to about 100%, about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about45%, about 40%, about 35%, about 30%, about 25%, about 20%, about 15, orabout 10%; about 10% to about 100%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about50%, about 45%, about 40%, about 35%, about 30%, about 25%, about 20%,or about 15%; about 15% to about 100%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about50%, about 45%, about 40%, about 35%, about 30%, about 25%, or about20%; about 20% to about 100%, about 95%, about 90%, about 85%, about80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%,about 45%, about 40%, about 35%, about 30%, or about 25%; about 25% toabout 100%, about 95%, about 90%, about 85%, about 80%, about 75%, about70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%,about 35%, or about 30%; about 30% to about 100%, about 95%, about 90%,about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about55%, about 50%, about 45%, about 40%, or about 35%; about 35% to about100%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%,about 65%, about 60%, about 55%, about 50%, about 45%, or about 40%;about 40% to about 100%, about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, orabout 45%; about 45% to about 100%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, toabout 50%; about 50% to about 100%, about 95%, about 90%, about 85%,about 80%, about 75%, about 70%, about 65%, about 60%, to about 55%;about 55% to about 100%, about 95%, about 90%, about 85%, about 80%,about 75%, about 70%, about 65%, or about 60%; about 60% to about 100%,about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, orabout 65%; about 65% to about 100%, about 95%, about 90%, about 85%,about 80%, about 75%, or about 70%; about 70% to about 100%, about 95%,about 90%, about 85%, about 80%, to about 75%; about 75% to about 100%,about 95%, about 90%, about 85%, or about 80%; about 80% to about 100%,about 95%, about 90%, or about 85%; about 85% to about 100%, about 95%,or about 90%; about 90% to about 100% or about 95%; or about 95% toabout 100% (as compared to the rate of apoptosis in a solid tumor in acontrol subject having the same type of cancer and not having one ormore of the point mutations in a NTRK1 gene described herein or one ormore of the point mutations in a NTRK2 gene described herein or one ormore point mutations in a NTRK3 gene described herein, and administeredthe same at least one Trk inhibitor).

Exemplary methods of determining the presence of a Trkinhibitor-resistant cancer in a subject are provided herein.

Trk Inhibitors

A variety of Trk inhibitors are known in the art. The ability of a Trkinhibitor to act as a Trk inhibitor may be tested using one or both ofthe assays described in Examples A and B in U.S. Pat. No. 8,513,263,which is incorporated herein by reference.

A Trk inhibitor can have an IC₅₀ of about 0.1 nM to about 50 μM, about45 μM, about 40 μM, about 35 μM, about 30 μM, about 25 μM, about 20 μM,about 15 μM, about 10 μM, about 5 μM, about 1 μM, about 950 nM, about900 nM, about 850 nM, about 800 nM, about 750 nM, about 700 nM, about650 nM, about 600 nM, about 550 nM, about 500 nM, about 450 nM, about400 nM, about 350 nM, about 300 nM, about 250 nM, about 200 nM, about150 nM, about 100 nM, about 80 nM, about 60 nM, about 40 nM, about 20nM, about 10 nM, or about 5 nM; about 1 nM to about 50 μM, about 45 μM,about 40 μM, about 35 μM, about 30 μM, about 25 μM, about 20 μM, about15 μM, about 10 μM, about 5 μM, about 1 μM, about 950 nM, about 900 nM,about 850 nM, about 800 nM, about 750 nM, about 700 nM, about 650 nM,about 600 nM, about 550 nM, about 500 nM, about 450 nM, about 400 nM,about 350 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM,about 100 nM, about 80 nM, about 60 nM, about 40 nM, about 20 nM, about10 nM, or about 5 nM; about 5 nM to about 50 μM, about 45 μM, about 40μM, about 35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM,about 10 μM, about 5 μM, about 1 μM, about 950 nM, about 900 nM, about850 nM, about 800 nM, about 750 nM, about 700 nM, about 650 nM, about600 nM, about 550 nM, about 500 nM, about 450 nM, about 400 nM, about350 nM, about 300 nM, about 250 nM, about 200 nM, about 150 nM, about100 nM, about 80 nM, about 60 nM, about 40 nM, about 20 nM, or about 10nM; about 10 nM to about 50 μM, about 45 μM, about 40 μM, about 35 μM,about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM, about 5μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM,about 750 nM, about 700 nM, about 650 nM, about 600 nM, about 550 nM,about 500 nM, about 450 nM, about 400 nM, about 350 nM, about 300 nM,about 250 nM, about 200 nM, about 150 nM, about 100 nM, about 80 nM,about 60 nM, about 40 nM, or about 20 nM; about 20 nM to about 50 μM,about 45 μM, about 40 μM, about 35 μM, about 30 μM, about 25 μM, about20 μM, about 15 μM, about 10 μM, about 5 μM, about 1 μM, about 950 nM,about 900 nM, about 850 nM, about 800 nM, about 750 nM, about 700 nM,about 650 nM, about 600 nM, about 550 nM, about 500 nM, about 450 nM,about 400 nM, about 350 nM, about 300 nM, about 250 nM, about 200 nM,about 150 nM, about 100 nM, about 80 nM, about 60 nM, or about 40 nM;about 40 nM to about 50 μM, about 45 μM, about 40 μM, about 35 μM, about30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM, about 5 μM,about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM,about 750 nM, about 700 nM, about 650 nM, about 600 nM, about 550 nM,about 500 nM, about 450 nM, about 400 nM, about 350 nM, about 300 nM,about 250 nM, about 200 nM, about 150 nM, about 100 nM, about 80 nM, orabout 60 nM; about 60 nM to about 50 μM, about 45 μM, about 40 μM, about35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM,about 5 μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM, about800 nM, about 750 nM, about 700 nM, about 650 nM, about 600 nM, about550 nM, about 500 nM, about 450 nM, about 400 nM, about 350 nM, about300 nM, about 250 nM, about 200 nM, about 150 nM, about 100 nM, or about80 nM; about 80 nM to about 50 μM, about 45 μM, about 40 μM, about 35μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM,about 5 μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM, about800 nM, about 750 nM, about 700 nM, about 650 nM, about 600 nM, about550 nM, about 500 nM, about 450 nM, about 400 nM, about 350 nM, about300 nM, about 250 nM, about 200 nM, about 150 nM, to about 100 nM; about100 nM to about 50 μM, about 45 μM, about 40 μM, about 35 μM, about 30μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM, about 5 μM,about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM,about 750 nM, about 700 nM, about 650 nM, about 600 nM, about 550 nM,about 500 nM, about 450 nM, about 400 nM, about 350 nM, about 300 nM,about 250 nM, about 200 nM, or about 150 nM; about 150 nM to about 50μM, about 45 μM, about 40 μM, about 35 μM, about 30 μM, about 25 μM,about 20 μM, about 15 μM, about 10 μM, about 5 μM, about 1 μM, about 950nM, about 900 nM, about 850 nM, about 800 nM, about 750 nM, about 700nM, about 650 nM, about 600 nM, about 550 nM, about 500 nM, about 450nM, about 400 nM, about 350 nM, about 300 nM, about 250 nM, or about 200nM; about 200 nM to about 50 μM, about 45 μM, about 40 μM, about 35 μM,about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM, about 5μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM,about 750 nM, about 700 nM, about 650 nM, about 600 nM, about 550 nM,about 500 nM, about 450 nM, about 400 nM, about 350 nM, about 300 nM, orabout 250 nM; about 250 nM to about 50 μM, about 45 μM, about 40 μM,about 35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about10 μM, about 5 μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM,about 800 nM, about 750 nM, about 700 nM, about 650 nM, about 600 nM,about 550 nM, about 500 nM, about 450 nM, about 400 nM, about 350 nM, orabout 300 nM; about 300 nM to about 50 μM, about 45 μM, about 40 μM,about 35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about10 μM, about 5 μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM,about 800 nM, about 750 nM, about 700 nM, about 650 nM, about 600 nM,about 550 nM, about 500 nM, about 450 nM, about 400 nM, or about 350 nM;about 350 nM to about 50 μM, about 45 μM, about 40 μM, about 35 μM,about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM, about 5μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM,about 750 nM, about 700 nM, about 650 nM, about 600 nM, about 550 nM,about 500 nM, about 450 nM, or about 400 nM; about 400 nM to about 50μM, about 45 μM, about 40 μM, about 35 μM, about 30 μM, about 25 μM,about 20 μM, about 15 μM, about 10 μM, about 5 μM, about 1 μM, about 950nM, about 900 nM, about 850 nM, about 800 nM, about 750 nM, about 700nM, about 650 nM, about 600 nM, about 550 nM, about 500 nM, or about 450nM; about 450 nM to about 50 μM, about 45 μM, about 40 μM, about 35 μM,about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM, about 5μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM,about 750 nM, about 700 nM, about 650 nM, about 600 nM, about 550 nM, orabout 500 nM; about 500 nM to about 50 μM, about 45 μM, about 40 μM,about 35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about10 μM, about 5 μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM,about 800 nM, about 750 nM, about 700 nM, about 650 nM, about 600 nM, orabout 550 nM; about 550 nM to about 50 μM, about 45 μM, about 40 μM,about 35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about10 μM, about 5 μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM,about 800 nM, about 750 nM, about 700 nM, about 650 nM, or about 600 nM;about 600 nM to about 50 μM, about 45 μM, about 40 μM, about 35 μM,about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM, about 5μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM,about 750 nM, about 700 nM, or about 650 nM; about 650 nM to about 50μM, about 45 μM, about 40 μM, about 35 μM, about 30 μM, about 25 μM,about 20 μM, about 15 μM, about 10 μM, about 5 μM, about 1 μM, about 950nM, about 900 nM, about 850 nM, about 800 nM, about 750 nM, or about 700nM; about 700 nM to about 50 μM, about 45 μM, about 40 μM, about 35 μM,about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM, about 5μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM, about 800 nM,or about 750 nM; about 750 nM to about 50 μM, about 45 μM, about 40 μM,about 35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about10 μM, about 5 μM, about 1 μM, about 950 nM, about 900 nM, about 850 nM,or about 800 nM; about 800 nM to about 50 μM, about 45 μM, about 40 μM,about 35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about10 μM, about 5 μM, about 1 μM, about 950 nM, about 900 nM, or about 850nM; about 850 nM to about 50 μM, about 45 μM, about 40 μM, about 35 μM,about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM, about 5μM, about 1 μM, about 950 nM, or about 900 nM; about 900 nM to about 50μM, about 45 μM, about 40 μM, about 35 μM, about 30 μM, about 25 μM,about 20 μM, about 15 μM, about 10 μM, about 5 μM, about 1 μM, or about950 nM; about 950 nM to about 50 μM, about 45 μM, about 40 μM, about 35μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM, about 10 μM,about 5 μM, or about 1 μM; about 1 μM to about 50 μM, about 45 μM, about40 μM, about 35 μM, about 30 μM, about 25 μM, about 20 μM, about 15 μM,about 10 μM, or about 5 μM; about 5 μM to about 50 μM, about 45 μM,about 40 μM, about 35 μM, about 30 μM, about 25 μM, about 20 μM, about15 μM, or about 10 μM; about 10 μM to about 50 μM, about 45 μM, about 40μM, about 35 μM, about 30 μM, about 25 μM, about 20 μM, or about 15 μM;about 15 μM to about 50 μM, about 45 μM, about 40 μM, about 35 μM, about30 μM, about 25 μM, or about 20 μM; about 20 μM to about 50 μM, about 45μM, about 40 μM, about 35 μM, about 30 μM, or about 25 μM; about 25 μMto about 50 μM, about 45 μM, about 40 μM, about 35 μM, or about 30 μM;about 30 μM to about 50 μM, about 45 μM, about 40 μM, or about 35 μM;about 35 μM to about 50 μM, about 45 μM, or about 40 μM; about 40 μM toabout 50 μM or about 45 μM; or about 45 μM to about 50 μM. In someembodiments, the Trk inhibitor also inhibits one or both of TrkB andTrkC, in addition to TrkA.

A Trk inhibitor can bind to one or more of the sites on TrkA: theextracellular cysteine-rich region (domain 1), the extracellular leucinerich region (domain 2), the extracellular cysteine-rich region (domain3), the extracellular immunoglobulin-like region (domain 4), theextracellular immunoglobulin-like region (domain 5), the transmembraneregion, the intracellular kinase domain, an amino acid in the activesite, the ATP-binding pocket, the tyrosine substrate binding site, theactivation loop (e.g., the DFG motif of the activation loop), the kinaseinsert domain (KID) region (e.g., amino acids 603 to 623), the hingeregion of the kinase, the α-C helix in the catalytic domain, the N-lobelysine responsible for the stabilization of the α phosphate of the ATPsubstrate, the C-terminus (see, e.g., Bertrand et al., J. Mol. Biol.423:439-453, 2012), the α-D helix in the C-terminus, the α-E helix inthe C-terminus, an amino acid in the kinase domain that interacts with aligand in the ATP binding site (see, e.g., Cherry et al., Curr. Med.Chem. 11:663-673, 2004). For example, a Trk inhibitor can bind to domain5 or the intracellular kinase domain of a TrkA.

Non-limiting examples of Trk inhibitors are described below.

An example of a Trk inhibitor is a (e.g., crystalline form of, a liquidformulation including) the compound of Formula I:

or a pharmaceutically acceptable salt thereof. Another example of a Trkinhibitor is a crystalline form including the hydrogen sulfate salt ofthe compound of Formula I in a stable polymorph form, referred to ascrystalline form (Formula I-HS), which may be characterized, forexample, by its X-ray diffraction pattern (see, U.S. Patent ApplicationSer. Nos. 62/080,374 and 14/943,014, both of which are hereinincorporated by reference in their entirety). Additional physicalproperties of a Trk inhibitor of Formula I and methods of making a Trkinhibitor of Formula I are described in U.S. Patent Application Ser.Nos. 62/080,374 and 14/943,014 (both of which are herein incorporated byreference in its their entirety). In some embodiments, the compound ofFormula I is(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate or a polymorph thereof.

In some embodiments, crystalline form (I-HS) is characterized by havingXRPD diffraction peaks (2θ degrees) at 18.4±0.2, 20.7±0.2, 23.1±0.2, and24.0±0.2. In some embodiments, crystalline form (I-HS) is characterizedby having XRPD diffraction peaks (2θ degrees) at 10.7±0.2, 18.4±0.2,20.7±0.2, 23.1±0.2, and 24.0±0.2. In some embodiments, crystalline form(I-HS) is characterized by having XRPD diffraction peaks (2θ degrees) at10.7±0.2, 18.4±0.2, 19.2±0.2, 20.2±0.2, 20.7±0.2, 21.5±0.2, 23.1±0.2,and 24.0±0.2. In some embodiments, crystalline form (I-HS) ischaracterized by having XRPD diffraction peaks (2θ degrees) at 10.7±0.2,15.3±0.2, 16.5±0.2, 18.4±0.2, 19.2±0.2, 19.9±0.2, 20.2±0.2, 20.7±0.2,21.5±0.2, 22.1±0.2, 23.1±0.2, 24.0±0.2. 24.4±0.2, 25.6±0.2, 26.5±0.2,27.6±0.2, 28.2±0.2, 28.7±0.2, 30.8±0.2, and 38.5±0.2.

In some embodiments, the crystalline form exhibits an onset to maximumof about 193 to about 205° Celsius, as measured by differential scanningcalorimetry. In some embodiments, the crystalline form (I-HS) exhibits aheat of melting of about 2.415 mW, as measured by differential scanningcalorimetry.

In some embodiments, the Trk inhibitor is selected from the groupconsisting of:(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate;(R)—N-cyclopropyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;(6R,13S)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.17,11.02,6.020,24]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione; and(6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.02,6.07,12.021,25]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one.

Non-limiting examples of Trk inhibitors are described in U.S. Pat. No.8,513,263 and International Publication No. WO 2010/048314 both of whichare incorporated by reference in their entireties herein, and include acompound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H or (1-6C alkyl);

R² is NR^(b)R^(c), (1-4C)alkyl, (1-4C)fluoroalkyl, CF₃,(1-4C)hydroxyalkyl, -(1-4C alkyl)hetAr¹, -(1-4C alkyl)NH₂, -(1-4Calkyl)NH(1-4C alkyl), -(1-4C alkyl)N(1-4C alkyl)₂, hetAr², hetCyc¹,hetCyc², phenyl which is optionally substituted with NHSO₂(1-4C alkyl),or (3-6C)^(e)cycloalkyl which is optionally substituted with (1-4Calkyl), CN, OH, OMe, NH₂, NHMe, N(CH₃)₂, F, CF₃, CO₂(1-4C alkyl), CO₂H,C(═O)NR^(e)R^(f) or C(═O)OR^(g);

R^(b) is H or (1-6C alkyl);

R^(c) is H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr³, or phenyl, whereinsaid phenyl is optionally substituted with one or more substituentsindependently selected from halogen, CN, CF₃ and —O(1-4C alkyl),

or NR^(b)R^(c) forms a 4 membered heterocyclic ring having a ringnitrogen atom wherein said heterocyclic ring is optionally substitutedwith one or more substituents independently selected from halogen, OH,(1-4C alkyl), (1-4 C)alkoxy, —OC(═O)(1-4C alkyl), NH₂, —NHC(═O)O(1-4Calkyl) and (1-4C)hydroxyalkyl,

or NR^(b)R^(c) forms a 5-6 membered heterocyclic ring having a ringheteroatom which is nitrogen and optionally having a second ringheteroatom or group selected from N, O and SO₂, wherein the heterocyclicring is optionally substituted with one or more substituentsindependently selected from OH, halogen, CF₃, (1-4C)alkyl, CO₂(1-4Calkyl), CO₂H, NH₂, NHC(═O)O(1-4C alkyl) and oxo,

or NR^(b)R^(c) forms a 7-8 membered bridged heterocyclic ring having aring nitrogen atom and optionally having a second ring heteroatomselected from N and O, wherein said ring is optionally substituted withCO₂(1-4C alkyl);

hetAr¹ is a 5-membered heteroaryl ring having 1-3 ring nitrogen atoms;

hetAr² is 5-6 membered heteroaryl ring having at least one nitrogen ringatom and optionally having a second ring heteroatom independentlyselected from N and S, wherein said heteroaryl ring is optionallysubstituted with one or more substituents independently selected from(1-4C alkyl), halogen, -(1-4 C)alkoxy, and NH(1-4C alkyl);

hetCyc¹ is a carbon-linked 4-6 membered azacyclic ring optionallysubstituted with one or more substituents independently selected from(1-4C alkyl), and CO₂(1-4C alkyl);

hetCyc² is a pyridinone or pyridazinone ring which is optionallysubstituted with a substituent selected from (1-4C)alkyl;

hetAr³ is a 5-6 membered heteroaryl ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from (1-4C)alkyl;

R^(e) is H or (1-4C)alkyl;

R^(f) is H, (1-4C)alkyl, or (3-6C)cycloalkyl;

or NR^(e)R^(f) forms a 5-6-membered azacyclic ring optionally having anadditional ring heteroatom selected from N and O, wherein the azacyclicring is optionally substituted with OH;

R^(g) is H or (1-6C)alkyl;

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-4C)alkoxy, CF₃ and CHF₂, or (ii)a 5-6 membered heteroaryl ring having a ring heteroatom selected from Nand S, wherein said heteroaryl ring is optionally substituted with oneor more halogen atoms;

X is null, —CH₂—, —CH₂CH₂—, —CH₂O— or —CH₂NR^(d)—;

R^(d) is H or (1-4C alkyl);

R³ is H or (1-4C alkyl);

each R⁴ is independently selected from halogen, (1-4C)alkyl, OH,(1-4C)alkoxy, NH₂, NH(1-4C alkyl) and CH₂OH; and

n is 0, 1, 2, 3, 4, 5 or 6.

For example, a Trk inhibitor can include one or more compounds selectedfrom the group consisting of:

-   (R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   N-(5-(2-(3-fluorophenyl)-2-methylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   (R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-phenylurea;-   (R)—N-(5-(2-(2-(difluoromethyl)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   (R)—N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1-methyl-6-oxo-1,6-dihydropyridazine-3-carboxamide;-   (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide;-   (3R,4R)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3,4-dihydroxypyrrolidine-1-carboxamide;-   (S)—N-(5-((R)-2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-methylpiperazine-1-carboxamide;-   (R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide;-   (R)—N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;    and-   (R)-1-(4-chlorophenyl)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)urea,    or a pharmaceutically acceptable salt thereof.

Additional examples of Trk inhibitors are the substitutedpyrazolo[1,5-a] pyrimidine compounds described in U.S. Pat. No.8,791,123 and International Publication No. WO 2011/006074, both ofwhich are herein incorporated by reference in their entireties. Forexample, Trk inhibitors that are substituted pyrazolo[1,5-a]pyrimidinecompounds can have the general formula II:

or a salt thereof, wherein:

R¹ is H or (1-6C alkyl);

R² is H, (1-6C)alkyl, -(1-6C)fluoroalkyl, -(1-6C)difluoroalkyl,-(1-6C)trifluoroalkyl, -(1-6C)chloroalkyl, -(2-6C)chlorofluoroalkyl,-(2-6C)difluorochloroalkyl, -(2-6C)chlorohydroxyalkyl,-(1-6C)hydroxyalkyl, -(2-6C)dihydroxyalkyl, -(1-6C alkyl)CN, -(1-6Calkyl)SO₂NH₂, -(1-6C alkyl)NHSO₂(1-3C alkyl), -(1-6C alkyl)NH₂, -(1-6Calkyl)NH(1-4C alkyl), -(1-6C alkyl)N(1-4C alkyl)₂, -(1-6Calkyl)NHC(═O)O(1-4C alkyl), -(1-6C alkyl)hetCyc¹, -(1-6C alkyl)hetAr¹,hetAr², hetCyc², —O(1-6C alkyl) which is optionally substituted withhalogen, OH or (1-4C)alkoxy, —O(3-6C cycloalkyl), Cyc¹, -(1-6Calkyl)(3-6C cycloalkyl), -(1-6C alkyl)(1-4C alkoxy), -(1-6Chydroxyalkyl)(1-4C alkoxy), a bridged 7-membered cycloalkyl ringoptionally substituted with (1-6C)hydroxyalkyl, or a bridged 7-8membered heterocyclic ring having 1-2 ring nitrogen atoms;

or NR¹R² forms a 4-6 membered azacyclic ring optionally substituted withone or more substituents independently selected from (1-6C)alkyl, OH,CO₂H, (1-3C alkyl)CO₂H, —O(1-6C alkyl), and (1-6C)hydroxyalkyl;

hetCyc¹ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O, wherein hetCyc¹ is optionallysubstituted with oxo, OH, halogen, or (1-6C)alkyl;

hetCyc² is a 6 membered carbon-linked heterocyclic ring having 1-2 ringheteroatoms independently selected from N and O, wherein hetCyc² isoptionally substituted with F, SO₂NH₂, SO₂(1-3C alkyl), or halogen;

hetAr¹ is a 5-membered heteroaryl ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with(1-4C)alkyl;

hetAr² is a 5-6 membered heteroaryl ring having 1-2 ring nitrogen atomsand optionally substituted with one or more substituents independentlyselected from (1-4C)alkyl, (3-6C)cycloalkyl, halogen, and OH;

Cyc¹ is a 3-6 membered cycloalkyl ring which is optionally substitutedwith one or more substituents independently selected from -(1-4C alkyl),—OH, —OMe, —CO₂H, -(1-4C alkyl)OH, halogen, and CF₃;

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-4C)alkoxy, —CF₃, —CHF₂, —O(1-4Calkyl)hetCyc³, -(1-4C alkyl)hetCyc³, —O(1-4C alkyl)O(1-3C alkyl) and—O(3-6C dihydroxyalkyl), or (ii) a 5-6 membered heteroaryl ring having aring heteroatom selected from N and S, wherein the heteroaryl ring isoptionally substituted with one or more substituents independentlyselected from halogen, —O(1-4C alkyl), (1-4C)alkyl, and NH₂, or (iii) apyrid-2-on-3-yl ring optionally substituted with one or moresubstituents independently selected from halogen and (1-4C)alkyl;

hetCyc³ is a 5-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with(1-6C)alkyl;

X is —CH₂—, —CH₂CH₂—, —CH₂O—, or —CH₂NR^(d)—;

R^(d) is H or -(1-4C alkyl);

R³ is H or -(1-4C alkyl);

each R⁴ is independently selected from halogen, -(1-4C)alkyl, —OH,-(1-4C)alkoxy, —NH₂, —NH(1-4C alkyl), and —CH₂OH; and

n is 0, 1, 2, 3, 4, 5, or 6.

For example, a Trk inhibitor can include one or more compounds selectedfrom the group consisting of:

-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-((2S)-bicyclo[2.2.1]heptan-2-yl)-5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(2-oxoimidazolidin-1-yl)ethyl)pyrazole[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((R)-2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-tert-butyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;    and-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;    or a pharmaceutically acceptable salt thereof.

Additional examples of Trk inhibitors are the macrocyclic compoundsdescribed in U.S. Pat. No. 8,933,084 and International Publication No.WO 2011/146336, both of which are herein incorporated by reference intheir entireties. For example, Trk inhibitors that are macrocycliccompounds can have the general formula III:

or a pharmaceutically acceptable salt thereof, wherein:

-   -   ring A is selected from rings A-I, A-2, and A-3 having the        structures:

wherein the wavy line labeled 1 indicates the point of attachment ofring A to ring B and the wavy line labeled 2 indicates the point ofattachment of ring A to W;

X is N or CH;

Y is H or F;

R¹ is H, (1-3C)alkoxy, or halogen;

ring B is selected from rings B-1 and B-2 having the structures:

wherein the wavy line labeled 3 indicates the point of attachment toring A and the wavy line labeled 4 indicates the point of attachment tothe pyrazolo[I,5-a]pyrimidine ring of Formula III;

W is O, NH, or CH₂, wherein when ring A is A-2, then W is CH₂;

m is 0, 1, or 2;

D is carbon, R² and R^(2a) are independently H, F, (1-3 C)alkyl or OH(provided that R² and R^(2a) are not both OH), and R³ and R^(3a) areindependently H, (1-3 C)alkyl or hydroxy(1-3 C)alkyl, or

D is carbon or nitrogen, R² and R³ are absent, and R^(2a) and R^(3a)together with the atoms to which they are attached form a 5-6 memberedheteroaryl ring having 1-2 ring heteroatoms;

Z is *—NR^(4a)C(═O)—, *—ONHC(═O)—, *—NR^(4b)CH₂— or *—OC(═O)—, whereinthe asterisk indicates the point of attachment of Z to the carbonbearing R³;

R^(4a) is H, (I-6C)alkyl, fluoro(I-6C)alkyl, difluoro(I-6C)alkyl,trifluoro(I-6C)alkyl, hydroxy(1-6C alkyl), or dihydroxy(2-6C alkyl);

R^(4b) is H, (1-6C)alkyl, fluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C alkyl), dihydroxy(2-6C alkyl), (1-6Calkyl)C(O)—, (3-6C cycloalkyl)C(O)—, Ar¹C(O)—, HOCH₂C(O)—, (1-6Calkyl)sulfonyl, (3-6C cycloalkyl)sulfonyl, Ar²(SO₂)—, HO₂CCH₂—, or (1-6Calkyl)NH(CO)—;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-6C)alkyl, and (1-6C)alkoxy; and

R⁵ and R⁶ are independently H, halogen, OH, (1-6C)alkyl, orhydroxy(1-6C)alkyl.

For example, a Trk inhibitor can include one or more compounds selectedfrom the group consisting of:

-   (6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),    7,9,11,19(26),20,23-heptaen-18-one;-   (6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0^(2,6).0^(7,12).0^(22,26)]    hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),    7,9,11,18(25), 19,22-heptaen-17-one;-   (6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0^(2,6).0^(7,12).0^(23,27)]heptacosa-1(26),    7,9,11,20(27),21,24-heptaen-19-one;-   (6R,13S)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo    [15.5.2.1^(7,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;-   (6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;-   (6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;-   (6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;-   (6R)-9-fluoro-(15R)-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;-   (6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;-   (6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo    [17.5.2.0^(2,6).0^(7,12).0^(22,26)]    hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one; and-   (6R)-9-fluoro-15,15-dimethyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;    or a pharmaceutically acceptable salt thereof.

Additional examples of Trk inhibitors are the substitutedimidazo[1,2-b]pyridazine compounds described in U.S. Pat. No. 8,450,322and International Publication No. WO 2010/033941, both of which areherein incorporated by reference in their entireties. For example, Trkinhibitors that are substituted imidazo[1,2B]pyridazine compounds canhave the general formula

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H or (1-6C alkyl);

R² is NR^(b)R^(c), (1-4C)alkyl, (1-4C)fluoroalkyl, CF₃,(1-4C)hydroxyalkyl, -(1-4C alkyl)hetAr¹, -(1-4C alkyl)NH(1-4C alkyl),hetAr², hetCyc¹, hetCyc², phenyl which is optionally substituted withNHSO₂(1-4C alkyl), or (3-6C)cycloalkyl which is optionally substitutedwith (1-4C alkyl), CN, OH, CF₃, CO₂(1-4C alkyl) or CO₂H;

R^(b) is H or (1-6C alkyl);

R^(c) is H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr³, or phenyl, whereinsaid phenyl is optionally substituted with one or more substituentsindependently selected from halogen, CN, CF₃ and —O(1-4C alkyl),

or NR^(b)R^(c) forms a 4 membered heterocyclic ring having a ringnitrogen atom, wherein said heterocyclic ring is optionally substitutedwith one or more substituents independently selected from halogen, OH,(1-4C alkyl), (1-4 C)alkoxy, —OC(═O)(1-4C alkyl), NH₂, —NHC(═O)O(1-4Calkyl), and (1-4C)hydroxyalkyl,

or NR^(b)R^(c) forms a 5-6 membered heterocyclic ring having a ringheteroatom which is nitrogen and optionally having a second ringheteroatom or group selected from N, O, and SO₂, wherein theheterocyclic ring is optionally substituted with one or moresubstituents independently selected from OH, halogen, CF₃, (1-4C)alkyl,CO₂(1-4C alkyl), CO₂H, NH₂, NHC(═O)O(1-4C alkyl), and oxo,

or NR^(b)R^(c) forms a 7-8 membered bridged heterocyclic ring having 1-2ring nitrogen atoms and optionally substituted with CO₂(1-4C alkyl);

-   -   hetAr¹ is a 5-membered heteroaryl ring having 1-3 ring nitrogen        atoms;    -   hetAr² is 5-6 membered heteroaryl ring having at least one        nitrogen ring atom and optionally having a second ring        heteroatom independently selected from N and S, wherein said        heteroaryl ring is optionally substituted with one or more        substituents independently selected from (1-4C alkyl), halogen,        -(1-4 C)alkoxy, and NH(1-4C alkyl);

hetCyc¹ is a carbon-linked 4-6 membered azacyclic ring optionallysubstituted with one or more substituents independently selected from(1-4C alkyl), CO₂H and CO₂(1-4C alkyl);

hetCyc² is a pyridinone or pyridazinone ring substituted with asubstituent selected from (1-4C)alkyl;

hetAr³ is a 5-6 membered heteroaryl ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from (1-4C)alkyl;

Y is a phenyl ring optionally substituted with one or more substituentsindependently selected from halogen, (1-4C)alkoxy, CF₃ and CHF₂, or a5-6 membered heteroaryl ring having a ring heteroatom selected from Nand S;

X is null, —CH₂—, —CH₂CH₂—, —CH₂O—, or —CH₂NR^(d)—;

R^(d) is H or (1-4C alkyl);

R³ is H or (1-4C alkyl);

each R⁴ is independently selected from halogen, (1-4C)alkyl, OH, (1-4C)alkoxy, NH₂, NH(1-4C alkyl), and CH₂OH; and

n is 0, 1, 2, 3, 4, 5, or 6.

Additional examples of Trk inhibitors are the substitutedpyrazolo[1,5-a]pyrimidine compounds described in WO 10/048314, hereinincorporated by reference in its entirety. For example, Trk inhibitorsthat are substituted pyrazolo[1,5-a]pyrimidine compounds can have thegeneral formula V:

or a pharmaceutically acceptable salt thereof, wherein:

R¹ is H or (1-6C alkyl);

R² is NR^(b)R^(c), (1-4C)alkyl, (1-4C)fluoroalkyl, CF₃,(1-4C)hydroxyalkyl, -(1-4C alkyl)hetAr¹, -(1-4C alkyl)NH₂, -(1-4Calkyl)NH(1-4C alkyl), -(1-4C alkyl)N(1-4C alkyl)₂, hetAr², hetCyc^(t),hetCyc², phenyl which is optionally substituted with NHSO₂(1-4C alkyl),or (3-6C)cycloalkyl which is optionally substituted with (1-4C alkyl),CN, OH, OMe, NH₂, NHMe, N(CH₃)₂, F, CF₃, CO₂(1-4C alkyl), CO₂H,C(═O)NR^(e)R^(f) or C(═O)OR^(g);

R^(b) is H or (1-6C alkyl);

R^(c) is H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr³, or phenyl, whereinsaid phenyl is optionally substituted with one or more substituentsindependently selected from halogen, CN, CF₃, and —O(1-4C alkyl),

or NR^(b)R^(c) forms a 4 membered heterocyclic ring having a ringnitrogen atom, wherein said heterocyclic ring is optionally substitutedwith one or more substituents independently selected from halogen, OH,(1-4C alkyl), (1-4 C)alkoxy, —OC(═O)(1-4C alkyl), NH₂, —NHC(═O)O(1-4Calkyl), and (1-4C)hydroxyalkyl,

or NR^(b)R^(c) forms a 5-6 membered heterocyclic ring having a ringheteroatom which is nitrogen and optionally having a second ringheteroatom or group selected from N, O, and SO₂, wherein theheterocyclic ring is optionally substituted with one or moresubstituents independently selected from OH, halogen, CF₃, (1-4C)alkyl,CO₂(1-4C alkyl), CO₂H, NH₂, NHC(═O)O(1-4C alkyl), and oxo,

or NR^(b)R^(c) forms a 7-8 membered bridged heterocyclic ring having aring nitrogen atom and optionally having a second ring heteroatomselected from N and O, wherein the ring is optionally substituted withCO₂(1-4C alkyl);

hetAr¹ is a 5-membered heteroaryl ring having 1-3 ring nitrogen atoms;

hetAr² is 5-6 membered heteroaryl ring having at least one nitrogen ringatom and optionally having a second ring heteroatom independentlyselected from N and S, wherein said heteroaryl ring is optionallysubstituted with one or more substituents independently selected from(1-4C alkyl), halogen, -(1-4 C)alkoxy and NH(1-4C alkyl);

hetCyc¹ is a carbon-linked 4-6 membered azacyclic ring optionallysubstituted with one or more substituents independently selected from(1-4C alkyl) and CO₂(1-4C alkyl);

hetCyc² is a pyridinone or pyridazinone ring which is optionallysubstituted with a substituent selected from (1-4C)alkyl;

hetAr³ is a 5-6 membered heteroaryl ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from (1-4C)alkyl;

R^(e) is H or (1-4C)alkyl;

R^(f) is H, (1-4C)alkyl, or (3-6C)cycloalkyl;

or NR^(e)R^(f) forms a 4-6-membered azacyclic ring optionally having anadditional ring heteroatom selected from N and O, wherein the azacyclicring is optionally substituted with OH;

R^(g) is H or (1-6C)alkyl;

Y is (i) phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-4C)alkoxy, CF₃, and CHF₂, or(ii) a 5-6 membered heteroaryl ring having a ring heteroatom selectedfrom N and S, wherein said heteroaryl ring is optionally substitutedwith one or more halogen atoms;

X is null, —CH₂—, —CH₂CH₂—, —CH₂O—, or —CH₂NR^(d)—;

R^(d) is H or (1-4C alkyl);

R³ is H or (1-4C alkyl);

each R⁴ is independently selected from halogen, (1-4C)alkyl, OH, (1-4C)alkoxy, NH₂, NH(1-4C alkyl), and CH₂OH; and

n is 0, 1, 2, 3, 4, 5, or 6.

For example, a Trk inhibitor can include one or more compounds selectedfrom the group consisting of:

-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-((2S)-bicyclo[2.2.1]heptan-2-yl)-5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(2-oxoimidazolidin-1-yl)ethyl)pyrazole[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((R)-2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-tert-butyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;    and-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;    or a pharmaceutically acceptable salt thereof.

Additional Trk inhibitors can be found in U.S. Publication No.2015/0166564 and WO 2012/158413, both of which are incorporated byreference in their entireties herein. For example, a Trk inhibitor canbe a compound of Formula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

the Y—B moiety and the NH—C(═X)—NH moiety are in the transconfiguration;

R^(a), R^(b), R^(c) and R^(d) are independently selected from H and(1-3C)alkyl;

X is O, S or NH;

R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl,dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3Calkylamino)(1-3C)alkyl, (1-4Calkoxycarbonyl)(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3Calkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3Calkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4Calkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl, hydroxycarbonyl(1-3Calkoxy)(1-6C)alkyl, hetAr⁵(CH₂)₀₋₁, or Ar⁵(CH₂)₀₋₁;

R² is H, F, or OH;

Y is a bond, —O— or —OCH₂—;

B is Art, hetAr¹, 1-6C alkyl or (1-6C)alkoxy;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, CF₃, CF₃O—, (1-4C)alkoxy,hydroxy(1-4C)alkyl, (1-6C)alkyl and CN;

hetAr¹ is a 5-6 membered heteroaryl having 1-3 ring heteroatomsindependently selected from N, S and O, and optionally substituted with1-2 groups independently selected form (1-6C)alkyl, halogen, OH, CF₃,NH₂ and hydroxy(1-2C)alkyl;

Ring C is formula C-1, C-2, or C-3

R³ is H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹,(3-7C)cycloalkyl, or hetAr²;

Ar² is phenyl optionally substituted with one or more groupsindependently selected from halogen, (1-6C)alkyl and hydroxymethyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more groups independently selected from (1-6C)alkyl and halogen;

R⁴ is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, amino-carbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxyl-carbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxytrifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxycyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, aminocarbonyl(1-6C)alkoxy,hydroxycarbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy,Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, Ar⁴, hetCyc²(O)CH₂—, (1-4C alkoxycarbonyl)(1-6C)alkoxy,hydroxycarbonyl(1-6C)alkoxy, aminocarbonyl(1-6C)alkoxy,hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C alkoxy)(1-6C)alkoxy,hydroxytrifluoro(1-6C)alkoxy, (1-3 C)alkyl sulfonamido(1-6C)alkoxy,(1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)aminocarboxy,hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxycarbonyl,aminocarbonyl, (1-3C alkoxy)amino-carbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)pyridinonyl, N-(1-3Ctrifluoroalkyl)pyridinonyl, (1-4C alkylsiloxy)(1-6C)alkoxy,isoindoline-1,3-dionyl(1-6C)alkoxy or N-(1-3C alkyl)oxadiazolonyl;

hetCyc² is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, and (1-6C)acyl;

hetCyc³ is a 4-7 membered heterocycle having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from F, CN, CF₃,(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-,(1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;

hetAr³ is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

Ar³ is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted with1-2 substituents independently selected from (1-6C)alkyl, halogen, CN,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy), (1-3C)trifluoroalkyl, andmethoxybenzyl; or a 9-10 membered bicyclic heteroaryl having 1-3 ringnitrogen atoms;

Ar⁴ is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—;

R⁵ is H, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, phenyl [optionally substitutedwith one or more groups independently selected from halogen, (1-6C)alkyland (1-6C)alkoxy], (3-4C)cycloalkyl, amino, aminocarbonyl, ortrifluoro(1-3C alky)amido; or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂;

hetAr⁵ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O or S, wherein the ring is optionallysubstituted with one or more substituents independently selected fromhalogen, (1-6C)alkyl, (1-6C)alkoxy and CF₃;

Ar⁵ is phenyl optionally substituted with one or more groupsindependently selected from halogen, (1-6C)alkyl, (1-6C)alkoxy, CF₃O—,(1-4C)alkoxycarbonyl and aminocarbonyl;

R^(3a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen, (1-6C)alkyl andhydroxymethyl, or a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, O and S and optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen;

R^(3b) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-6C)alkyl and hydroxymethyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moregroups independently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl, andmethoxybenzyl; and

R^(5a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen, (1-6C)alkyl andhydroxymethyl, or a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, O and S and optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen.

Further examples of Trk inhibitors can be found in InternationalPublication No. WO 2014078454, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound ofFormula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts, orsolvates thereof,wherein:X is O, S, NH or N—CN;Ring A is formula A-1 or A-2

-   Y is H, halogen, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkyl [optionally    substituted with 1-5 fluoros], cyano(1-6C)alkyl, hydroxy(1-6C)alkyl,    dihydroxy(2-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-6C)alkoxy    [optionally substituted with 1-5 fluoros], CN, aminocarbonyl or    (1-4C alkoxy)carbonyl;-   R^(a), R^(b) and R^(c) are independently selected from H, halogen,    (1-3C)alkyl, (1-3C)alkoxy and CN;-   B is NR¹, O, a bond, CR^(d)R^(e), S or SO₂;-   D is NR¹, O, a bond, CR^(f)R⁸, S or SO₂;-   E is NR¹, O, a bond, or CR^(h)R\S or SO₂;-   F is CR^(j)R^(k);-   provided that the ring formed by B, D, E, and F together with the    atoms to which they are attached contains at least five atoms and    zero or one of B, D or E is NR¹ or O;-   G is CR^(m)R^(n);-   K is NR¹; R¹ is (1-6C)alkyl [optionally substituted with one to five    fluoros], (1-6C)cycloalkyl [optionally substituted with one to five    fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one    to five fluoros], (1-6C)alkylC(═O)— or (1-6C alkoxy)C═O—;-   R^(d), R^(e), R^(f), R^(g), R^(h), R\R^(j) and R^(k) are    independently H, OH, (1-6C)alkyl [optionally substituted with one to    five fluoros], (3-6C)cycloalkyl [optionally substituted with one to    five fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with    one to five fluoros], hydroxy(2-6C)alkyl [optionally substituted    with one to five fluoros], (2-6C)cyanoalkyl, (1-6C)alkoxy    [optionally substituted with one to five fluoros], or (1-3C    alkoxy)(2-6C)alkoxy [optionally substituted with one to five    fluoros],-   or one of a pair of R^(d) and R^(e), or R^(f) and R⁸, or R^(h) and    R^(l), or R* and R^(k), together with the carbon atom to which they    are attached form a (3-6C)cycloalkyl, oxetanyl or azetidinyl ring,    or one of a pair of R^(d) and R^(e), or R^(f) and R⁸, or R^(h) and    R¹, or R^(j) and R^(k) form an oxo group,-   and wherein only one of R^(d) and R^(e) can be OH and neither is OH    if B is connected to a heteroatom, and only one of R^(f) and R⁸ can    be OH and neither is OH if D is connected to a heteroatom, and only    one of R^(h) and R′ can be OH and neither is OH if E is connected to    a heteroatom, and only one of R^(j) and R^(k) can be OH and neither    is OH if F is connected to a heteroatom;-   R^(m) is H, (1-3C)alkyl [optionally substituted with 1-5 fluoros],    cyclopropyl or cyclobutyl, and-   R″ is H or (1-3C)alkyl [optionally substituted with 1-5 fluoros], or-   R^(m) and R^(n) together form an oxo group;-   R^(p) is H, (1-6C)alkyl [optionally substituted with one to five    fluoros], (3-6C)cycloalkyl [optionally substituted with one to five    fluoros], (1-3C alkoxy)(2-6C)alkyl [optionally substituted with one    to five fluoros], hydroxy(2-6C)alkyl [optionally substituted with    one to five fluoros], or (2-6C)cyanoalkyl;-   Ring C is formula C-1 or C-2

-   R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹,    (3-7C)cycloalkyl, or hetAr²;-   Ar² is phenyl optionally substituted with one or more groups    independently selected from halogen and (1-6C)alkyl; hetCyc¹ is a    5-6-membered saturated or partially unsaturated heterocyclic ring    having 1-2 ring heteroatoms independently selected from N and O;-   hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms    independently selected from N, O and S and optionally substituted    with one or more groups independently selected from (1-6C)alkyl and    halogen;-   R⁴ is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,    trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,    cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3C    alkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, (1-3    C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,    hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,    (1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy,    trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy,    pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy,    dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy,    hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy,    hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy,    (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally    substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C    alkoxy)(1-6C)alkyl], hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4C    alkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,    aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3C    alkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkyl    sulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy, di(1-3C    alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl,    (1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl,    hydroxylcarbonyl, aminocarbonyl, (1-3C alkoxy)aminocarbonyl,    hetCyc³, halogen, CN, trifluoromethylsulfonyl, N-(1-3C    alkyl)oxadiazolonyl, hetAr⁵ or hetCyc⁴-O—;-   hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring    heteroatoms independently selected from N and O and optionally    substituted with 1-2 groups independently selected from (1-6C)alkyl,    (1-4C alkylcarboxy)(1-6C)alkyl, and (1-6C)acyl;-   hetCyc³ is a 4-7 membered heterocycle having 1-2 ring heteroatoms    independently selected from N and O and optionally substituted with    one or more substituents independently selected from F, CN,    (1-6C)alkyl, trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C    alkoxy)(1-6C)alkyl, (1-6C)acyl-, (1-6C)alkylsulfonyl,    trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl; hetAr³ is a    5-membered heteroaryl ring having 1-3 ring atoms independently    selected from N, O and S and optionally substituted with    (1-6C)alkyl;-   Ar³ is phenyl optionally substituted with (1-4C)alkoxy;-   hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms    independently selected from N, S and O and optionally substituted    with one or more substituents independently selected from    (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl,    difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C    cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,    (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C    alkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino,    difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4C    cycloalkyl)amino;-   hetAr⁵ is a group selected from the structures:

-   where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally    substituted with 1-3 fluoros), wherein each of said hetAr⁵ groups is    optionally further substituted with one or more groups independently    selected from F and (1-3C)alkyl optionally substituted with 1-3    fluoros;-   hetCyc⁴ is a 7-8 membered bridged heterocycle having a ring nitrogen    atom and optionally substituted with one or more groups    independently selected from (1-6C)alkyl and halogen;-   Ar⁴ is phenyl optionally substituted with one or more groups    independently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,    (1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,    hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C    alkoxy)(1-3C alkyl)OC(═O)—;-   R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,    trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl,    pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy,    hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)OC(═O)—,    (1-6C)alkylthio, (3-4C)cycloalkyl, amino, aminocarbonyl,    trifluoro(1-3C alkyl)amido, or phenyl (optionally substituted with    one or more groups independently selected from halogen, (1-6C)alkyl    and (1-6C)alkoxy); or-   R⁴ and R⁵ together with the atoms to which they are attached form a    5-6 membered saturated, partially unsaturated or unsaturated    carbocyclic ring optionally substituted with one or more    substituents independently selected from (1-6C)alkyl, or-   R⁴ and R⁵ together with the atoms to which they are attached form    5-6 membered saturated, partially unsaturated or unsaturated    heterocyclic ring having a ring heteroatom selected from N, O or S,    wherein said heterocyclic ring is optionally substituted with one or    two substituents independently selected from (1-6C alkyl)C(═O)O—,    (1-6C)acyl, (1-6C)alkyl and oxo, and said sulfur ring atom is    optionally oxidized to S(═O) or SO₂;-   R^(3a) is halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,    (3-6C)cycloalkyl, phenyl optionally substituted with one or more    substituents independently selected from halogen and (1-6C)alkyl, or    a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms    independently selected from N, O and S and optionally substituted    with one or more groups independently selected from (1-6C)alkyl and    halogen;-   R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl    [optionally substituted with one or more groups independently    selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,    (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,    hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C    alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 membered heteroaryl ring    having 1-3 ring heteroatoms independently selected from N, S and O    and optionally substituted with 1-2 substituents independently    selected from (1-6C)alkyl, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl,    (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—,    (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂,    (1-6C alkyl)amino, di(1-6C alkyl)amino and (1-3C    trifluoroalkoxy)(1-3C)trifluoroalkyl; and-   R^(5a) is halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,    (3-6C)cycloalkyl, phenyl optionally substituted with one or more    substituents independently selected from halogen and (1-6C)alkyl, or    a 5-6 membered heteroaryl ring having 1-3 ring heteroatoms    independently selected from N, O and S and optionally substituted    with one or more groups independently selected from (1-6C)alkyl and    halogen.

Further examples of Trk inhibitors can be found in InternationalPublication No. WO 2014078417, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound ofFormula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

-   X is O, S, NH or N—CN;-   Ring A is

-   R¹ is phenyl optionally substituted with one or more substituents    independently selected from halogen and (1-3C)alkyl;-   R² is (1-3C)alkyl [optionally substituted with 1 to 5 fluoros] or    (3-4C)cycloalkyl [optionally substituted with one or two fluoros];-   R⁶ is H or CH₃; Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl,or hetAr²;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from (1-6C)alkyl andhalogen; R⁴ is hetAr⁴, hetAr⁵ or hydroxy(1-6C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and substituted with one or moresubstituents independently selected from (1-6C)alkyl, halogen, CN,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, difluoro(1-6C)alkyl,fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3Ctrifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino,trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more substituents independently selectedfrom F and (1-3C)alkyl optionally substituted with 1-3 fluoros;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more substituents independently selected fromhalogen, (1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂; R is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, halogen, CN, CF₃, CF3O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^(5a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen.

Additional examples of Trk inhibitors can be found in InternationalPublication No. WO 2014078408, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound ofFormula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

X is O, S, NH or —N—CN;

Ring A is formula A-1 A-2, A-3 or A-4

R¹ is H, halogen, (1-3C)alkyl [optionally substituted with 1-5 fluoros],(1-3C)alkoxy [optionally substituted with 1-5 fluoros], or(3-5C)cycloalkyl;

Y is Ar¹ or hetAr¹;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-3C)alkyl [optionally substitutedwith 1-5 fluoros], and (1-3C)alkoxy [optionally substituted with 1-5fluoros];

hetAr¹ is pyridyl optionally substituted with one or more substituentsindependently selected from halogen, (1-3C)alkyl [optionally substitutedwith 1-5 fluoros], and (1-3C)alkoxy [optionally substituted with 1-5fluoros];

Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl,or hetAr²; Ar is phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl;hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from (1-6C)alkyl andhalogen;

R⁴ is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy,trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy,hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy,(1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy,di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl,(1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, and (1-6C)acyl;

hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from F, CN, (1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4Calkoxy)carbonyl;

hetAr³ is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl; AT³ is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted withone or more substituents independently selected from (1-6C)alkyl,halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl,difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino,difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4Ccycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more substituents independently selectedfrom F and (1-3C)alkyl optionally substituted with 1-3 fluoros;

Ar⁴ is phenyl optionally substituted with one or more substituentsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more substituents independently selected fromhalogen, (1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or R⁴ and R⁵ together with the atoms to whichthey are attached form 5-6 membered saturated, partially unsaturated orunsaturated heterocyclic ring having a ring heteroatom selected from N,O or S, wherein said heterocyclic ring is optionally substituted withone or two substituents independently selected from (1-6C alkyl)C(═O)O—,(1-6C)acyl, (1-6C)alkyl and oxo, and said sulfur ring atom is optionallyoxidized to S(═O) or SO₂;

R^(3a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^(5a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moresubstituents independently selected from (1-6C)alkyl and halogen.

Further examples of Trk inhibitors can be found in InternationalPublication No. WO 2014078378, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound ofFormula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

Ring B and the NH—C(═X)—NH moiety are in the trans configuration;

R^(a), R^(b), R^(c) and R^(d) are independently selected from H and(1-3C)alkyl,

or R^(c) and R^(d) are independently selected from H and (1-3C)alkyl,and R^(a) and R^(b) together with the atom to which they are attachedform a cyclopropyl ring;

X is O, S, NH or N—CN;

R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl,dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3Calkylamino)(1-3C)alkyl, (1-4Calkoxycarbonyl)(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3Calkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3Calkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4Calkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl, or hydroxycarbonyl(1-3Calkoxy)(1-6C)alkyl;

R² is H, F, or OH;

Ring B is Ar¹ or hetAr¹;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, CF₃, CF₃O—, (1-4C)alkoxy,hydroxy(1-4C)alkyl, (1-6C)alkyl and CN; hetAr¹ is a 5-6 memberedheteroaryl having 1-3 ring heteroatoms independently selected from N, Sand O, and optionally substituted with one or more groups independentlyselected from (1-6C)alkyl, halogen, OH, CF₃, NH₂ and hydroxy(1-2C)alkyl;

Ring C is selected from formulas C-1 through C-13:

R is H, NH₂, CN, halogen, (1-3C)alkyl [optionally substituted with 1 to3 fluoros],

H₂NC(═O)—, (1-3Calkyl)NHC(═O)—, di(1-3Calkyl)NHC(═OK hydroxy(1-3C)alkyl,CH3OCH2CH2, (3-4C)cycloalkyl or (1-3C)alkoxy;

R^(3a) is H, (1-3C)alkyl, CF₃CH₂CH₂, HCF₂CH₂CH₂, H₂FCCH₂CH₂, CF₃CH₂,HOCH₂CH₂, MeOCH₂CH₂, or (3-4C)cycloalkyl;

R⁴ is H, OH, (1-6C)alkyl [optionally substituted with 1-5 fluoros],cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy [optionally substituted with 1-5 fluoros],cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc (1-6C)alkoxy,hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy,(1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy,di(1-3C alkyl)amino-carboxy, hetCyc C(═O)O—, hydroxydifluoro(1-6C)alkyl,(1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

R^(4a) is H, (1-6C)alkyl, CF₃CH₂CH₂, HCF₂CH₂CH₂, H₂FCCH₂CH₂, CF₃CH₂,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(3-6C)cycloalkyl [optionally substituted with F, OH, (1-6C alkyl),(1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl], hetAr⁴, Ar⁴,hydroxydifluoro(1-6C)alkyl, (1-4C alkylcarboxy)(1-6C)alkyl, hetCyc³,N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, and (1-6C)acyl;

hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from F, CN, (1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4Calkoxy)carbonyl;

hetAr is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

Ar is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is independently a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, S and O and optionallysubstituted with one or more substituents independently selected from(1-6C)alkyl [optionally substituted with 1-3 fluoros], halogen, CN,hydroxy(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino, (1-3Ctrifluoroalkoxy), fluoro(1-6C alkyl)amino, difluoro(1-6C alkyl)amino,trifluoro(1-6C alkyl)amino, and (3-4C cycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more groups independently selected fromF and (1-3C)alkyl optionally substituted with 1-3 fluoros;

Ar⁴ is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—;

R⁵ is H, (1-6C)alkyl [optionally substituted with 1-5 fluoros], halogen,CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (1-4Calkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino, aminocarbonyl,trifluoro(1-3C alkyl)amido, or phenyl [optionally substituted with oneor more groups independently selected from halogen, (1-6C)alkyl and(1-6C)alkoxy];

R^(5a) is H, (1-6C)alkyl, CF₃CH₂CH₂, HCF₂CH₂CH₂, H₂FCCH₂CH₂, CF₃CH₂,hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl, (3-4C)cycloalkyl, orphenyl [optionally substituted with one or more groups independentlyselected from halogen, (1-6C)alkyl and (1-6C)alkoxy];

R is (1-6C)alkyl, (3-6C)cycloalkyl, or phenyl [optionally substitutedwith one or more groups independently selected from halogen,(1-6C)alkyl, (1-6C)alkoxy, (3-4C)cycloalkyl, amino, aminocarbonyl, andtrifluoro(1-3C)alkylamido];

R^(8a) and R^(8b) are independently H, halogen, CN, NH₂, (1-6C)alkyl[optionally substituted with 1-5 fluoros], (1-6C)alkoxy, (1-3Calkoxy)(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkoxy, (1-6C alkyl)sulfonyl,(3-6C cycloalkyl)sulfonyl, (3-4C)cycloalkyl, amino, (1-6Calkyl)NH—,phenyl [optionally substituted with (1-6C alkyl)SO₂—] or hetAr⁴, whereinonly one of R^(8a) and R^(8b) can be phenyl [optionally substituted with(1-6C alkyl)SO₂—] or hetAr⁴;

R⁹ is H, (1-6C)alkyl, CF₃CH₂—, CF₃CH₂CH₂—, (1-3Calkoxy)(1-6C)alkyl or(3-4C)cycloalkyl; and

R¹⁰ is (3-6C)cycloalkyl or phenyl [optionally substituted with one ormore substituents independently selected from halogen, (1-6C)alkyl,(1-6C)alkoxy, (3-4C)cycloalkyl, amino, aminocarbonyl and trifluoro(1-3Calkyl)amido].

Additional examples of Trk inhibitors can be found in InternationalPublication No. WO 2014078372, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound ofFormula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

Ring B and the NH—C(═X)—NH moiety are in the trans configuration;

R^(a), R^(b), R^(c) and R^(d) are independently selected from H and(1-3C)alkyl,

or R^(c) and R^(d) are independently selected from H and (1-3C)alkyl,and R^(a) and R^(b) together with the atom to which they are attachedform a cyclopropyl ring;

X is O, S, NH or N—CN;

R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl,dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3C)alkylamino(1-3C)alkyl, (1-4C)alkoxycarbonyl(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3Calkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3Calkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4Calkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl, or hydroxycarbonyl(1-3Calkoxy)(1-6C)alkyl;

R² is H, F, or OH;

Ring B is Ar¹ or hetAr¹;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, CF₃, CF₃O—, (1-4C)alkoxy,hydroxy(1-4C)alkyl, (1-6C)alkyl and CN; hetAr¹ is a 5-6 memberedheteroaryl having 1-3 ring heteroatoms independently selected from N, Sand O, and optionally substituted with one or more groups independentlyselected from (1-6C)alkyl, halogen, OH, CF₃, NH₂ and hydroxy(1-2C)alkyl;

Ring C is selected from formulas C-1 through C-9

R is H, halogen, or phenyl [optionally substituted with one or moresubstituents independently selected from halogen and (1-3C)alkyl];

R^(7a) and R^(7b) are independently H, (1-6C)alkyl, or phenyl[optionally substituted with one or more substituents independentlyselected from halogen and (1-3C)alkyl], wherein only one of R^(7a) andR^(7b) can be phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-3C)alkyl;

R⁸ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, (1-3C)alkyl and (3-6C)cycloalkyl;

R⁹ is H, halogen, (1-6C)alkyl [optionally substituted with one to fivefluoros] or (1-6C)alkoxy; and

R¹⁰ is H or (1-6C)alkyl.

Further examples of Trk inhibitors can be found in InternationalPublication No. WO 2014078331, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound ofFormula I-C:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

X is O, S, NH or N—CN;

Ring A is formula A-1 or A-2

wherein the dashed lines are optional double bonds;

n is 0 or 1 when Ring A is formula A-1, and n is 0 when Ring A isformula A-2;

G¹, G² and G³ are independently CR^(X) or N, wherein no more than 2 ofG¹, G² and G³ can be N;

each R^(x) is independently H, halogen, (1-4C)alkyl or (1-4C)alkoxy;

R¹ is H, halogen, (1-3C)alkoxy(1-3C)alkyl (optionally substituted with1-5 fluoros), (1-3C alkyl)sulfanyl(1-3C)alkyl (optionally substitutedwith 1-5 fluoros), (1-3C)alkyl (optionally substituted with 1-5fluoros), (1-3C)alkoxy (optionally substituted with 1-5 fluoros), (1-3Calkyl)sulfanyl (optionally substituted with 1-5 fluoros),cyano(1-3C)alkyl (optionally substituted with 1-5 fluoros),hydroxy(1-3C)alkyl (optionally substituted with 1-5 fluoros),(1-4C)alkyl (optionally substituted with 1-5 fluoros), CH₃CH₂NR^(y),CF₃CH₂NR^(y), HCF₂CH₂NR^(y), H₂CFCH₂NR^(y), CH₃NR^(y)CH₂,R^(y)R^(y)NCH₂CH₂, R^(y)R^(y)NCH₂CFH, or

R^(y)R^(y)NCH₂CF₂;

each R^(y) is independently H or methyl;

when n is 0, R is selected from the group consisting of H, halogen,(1-6C)alkyl

[optionally substituted with 1-5 fluoros], (1-6C)alkoxy [optionallysubstituted with 1-5 fluoros], (1-3C alkoxy)(1-4C)alkyl, (3-6Ccycloalkyl)CH₂O—, amino(1-3C)alkyl,

CF₃CH₂NHCH₂, HCF₂CH₂NHCH₂, a C5-C8 bridged cycloalkyl, hetCyc³,hetCyc^(a)CH₂, Cyc^(a), hetAr¹ and Ar¹, and

when n is 1, R is selected from the group consisting of H, halogen, CF₃,F₂CH, FCH₂, methyl and methoxy.

hetCyc³ is a 4-6 membered heterocyclic ring having a ring heteroatomselected from N, O and S and optionally substituted with 1-3 groupsindependently selected from OH, F, (1-6C)alkoxy or (1-6C)alkyl[optionally substituted with 1-3 fluoros];

Cyc^(a) is a (3-6C)cycloalkyl optionally substituted with (1-4C)alkoxy,(1-4C)alkyl, F or OH;

hetAr¹ is a 5-6 membered heteroaryl having 1-3 ring heteroatomsindependently selected from N, S and O, and optionally substituted with1-2 groups independently selected from (1-6C)alkyl, halogen, OH, CF₃,NH₂ and hydroxy(1-2C)alkyl;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, CF₃, CF₃O—, (1-4C)alkoxy,(1-4C)sulfanyl, hydroxy(1-4C)alkyl, (1-6C)alkyl and CN;

R^(a) is H, (1-3C)alkyl, cyclopropyl, cyclobutyl, or CF₃, and

R^(b) is H, methyl or ethyl,

or R^(a) and R^(b) together with the carbon atom to which they areattached form a 3-6 membered cycloalkyl ring;

R^(c) is H, methyl or ethyl

R^(d) is CF₃CH₂CH₂, phenyl or phenylCH₂— wherein each phenyl ring isoptionally substituted with one or more substituents independentlyselected from halogen, methoxy and methoxymethyl;

Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl, aC5-C8 bridged cycloalkyl, or hetAr²;

Ar² is phenyl optionally substituted with one or more groupsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O;

hetAr is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more groups independently selected from (1-6C)alkyl and halogen;

R⁴ is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl,

aminocarbonyl(1-6C)alkyl, (1-3C)alkylsulfonamido(1-6C)alkyl,sulfamido(1-6C)alkyl, hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl,Ar³(1-6C)alkyl, (1-6C)alkoxy,

monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy, trifluoro(1-6C)alkoxy,tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy, cyano(1-6C)alkoxy,hydroxy(1-6C)alkoxy,

dihydroxy(2-6C)alkoxy, amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy,hetCyc²(1-6C)alkoxy, hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4Calkoxy)(1-6C)alkoxy, (1-3C alkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl[optionally substituted with F, OH, (1-6C alkyl), (1-6C) alkoxy, or(1-3C alkoxy)(1-6C)alkyl], hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy,

hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy,(1-3C)alkylamido(1-6C)alkoxy, di(1-3C alkyl)amino-carboxy,hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, hetAr⁵, Ar⁴—O—,hetCyc⁴-O—, Cyc′-O—, or aminohydroxy(1-6C)alkoxy; hetCyc² is a 4-6membered heterocyclic ring having 1-2 ring heteroatoms

independently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, 1-4C alkoxy)carbonyl,(1-6C)acyl, halogen and oxo;

hetCyc is a 4-7 membered heterocycle having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents

independently selected from F, CN, (1-6C)alkyl, trifluoro(1-6C)alkyl,hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-,(1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;

hetCyc⁴ is a 5-8 membered monocyclic, spirocyclic or bridged heterocyclehaving a ring nitrogen atom and optionally substituted with one or moregroups independently selected from (1-6C)alkyl and halogen;

Cyc¹ is a 3-6 membered carbocycle optionally substituted with an aminogroup; hetAr³ is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

Ar is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted withone or more substituents independently selected from (1-6C)alkyl,halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl,difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino,difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4Ccycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more groups independently selected fromF and (1-3C)alkyl optionally substituted with 1-3 fluoros;

Ar⁴ is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more groups independently selected from halogen,(1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂;

R^(3a) is halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl, or a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and optionally substituted with one or more groupsindependently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^(5a) is halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl, or a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and optionally substituted with one or more groupsindependently selected from (1-6C)alkyl and halogen.

Additional examples of Trk inhibitors can be found in InternationalPublication No. WO 2014078328, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound ofFormula I-1:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

Ring A is selected from formulas A-1, A-2, A-3 or A-4:

R¹ is H, halogen, (1-3C)alkoxy(1-3C)alkyl [optionally substituted with1-5 fluoros], (1-3C alkyl)sulfanyl(1-3C)alkyl [optionally substitutedwith 1-5 fluoros], (1-3C)alkoxy [optionally substituted with 1-5fluoros], (1-3C alkyl)sulfanyl [optionally substituted with 1-5fluoros], cyano(1-3C)alkyl [optionally substituted with 1-5 fluoros],hydroxy(1-3C)alkyl [optionally substituted with 1-5 fluoros],(1-4C)alkyl [optionally substituted with 1-5 fluoros], CH₃CH₂NR^(a),CF₃CH₂NR^(a), HCF₂CH₂NR^(a), H₂CFCH₂NR^(a), CH₃NR^(a)CH₂, R{circumflexover ( )}{circumflex over ( )}CHzCHs or R{circumflex over( )}{circumflex over ( )}CHzCFz;

each R^(a) is independently H or methyl;

R^(x) and R^(y) are independently selected from H, halogen, (1-3C)alkyl[optionally substituted with 1-5 fluoros] or (1-3C)alkoxy [optionallysubstituted with 1-5 fluoros];

n is 0, 1 or 2;

m is 0, 1 or 2;

X is O, S, NH or N—CN;

Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl,or hetAr²;

Ar is phenyl optionally substituted with one or more groupsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O;

hetAr is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more groups independently selected from (1-6C)alkyl and halogen;

R⁴ is OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxytrifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy,hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy,(1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy,di(1-3C alkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl,(1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc³, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

hetCyc is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, and (1-6C)acyl; hetCyc is a 4-7 memberedheterocycle having 1-2 ring heteroatoms independently selected from Nand O and optionally substituted with one or more substituentsindependently selected from F, CN, (1-6C)alkyl, trifluoro(1-6C)alkyl,hydroxy(1-6C)aikyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-,(1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;hetAr³ is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl; Ar³ is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted withone or more substituents independently selected from (1-6C)alkyl,halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl,difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino,difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4Ccycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more groups independently selected fromF and (1-3C)alkyl optionally substituted with 1-3 fluoros;

Ar⁴ is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more groups independently selected from halogen,(1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or R⁴ and R⁵ together with the atoms to whichthey are attached form 5-6 membered saturated, partially unsaturated orunsaturated heterocyclic ring having a ring heteroatom selected from N,O or S, wherein said heterocyclic ring is optionally substituted withone or two substituents independently selected from (1-6C alkyl)C(—O)O—,(1-6C)acyl, (1-6C)alkyl and oxo, and said sulfur ring atom is optionallyoxidized to S(═O) or SO₂;

R^(3a) is halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl, or a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and optionally substituted with one or more groupsindependently selected from (1-6C)alkyl and halogen;

R^(4a) is (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionallysubstituted with one or more groups independently selected from(1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—,aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—,HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, S and O and optionally substituted with 1-2 substituentsindependently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl,trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino and(1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^(5a) is halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl, or a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and optionally substituted with one or more groupsindependently selected from (1-6C)alkyl and halogen.

Further examples of Trk inhibitors can be found in InternationalPublication No. WO 2014078325, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound ofFormula I:

or a stereoisomer, tautomer, or pharmaceutically acceptable salt,solvate or prodrug thereof, wherein:

Ring A is formula A-1, A-2, A-3, A-4, A-5 or A-6

m is 0, 1, 2, 3 or 4;

n is 0, 1, 2 or 3;

p is 0, 1 or 2;

R¹ is formula R¹-1, R¹-2 or R¹-3

Y¹ is CH₃CH₂—, CF₃CH₂—, CH₃O—, F₃CO—, F₂CHO—, FCH₂O—, CH₃S—, F₃CS—,F₂CHS—, or FCH₂S—;

Y² is O, S, NH, MeN— or CH₂;

Y³ is CH3O—, CH3S—, MeNH— or Me₂N—;

Y⁴ is CH₂ and Y⁵ is S or, or Y⁴ is S or O and Y⁵ is CH₂;

R² is halogen, (1-3C)alkyl (optionally substituted with 1-3 fluoros),(1-3C)alkoxy (optionally substituted with 1-3 fluoros), CH₃OCH₂—(optionally substituted with 1-3 fluoros), (1-3C alkyl)sulfanyl,di(1-3C)alkylamino, cyclopropyl, cyclobutyl or azetidinyl, wherein eachof said cyclopropyl, cyclobutyl and azetidinyl is optionally substitutedwith 1 to 2 fluoros;

X is O, S, NH or N—CN;

Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl,or hetAr²;

Ar² is phenyl optionally substituted with one or more groupsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more groups independently selected from (1-6C)alkyl and halogen;

R⁴ is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxytrifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxycyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy,hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy,(1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3C)alkylamido(1-6C)alkoxy,di(1-3C alkyl)amino-carboxy, hetCyc C(═O)O—, hydroxydifluoro(1-6C)alkyl,(1-4C alkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

hetCyc² is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, (1-6C)acyl and halogen;

hetCyc³ is a 4-7 membered heterocycle having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with oneor more substituents independently selected from F, CN, (1-6C)alkyl,trifluoro(1-6C)alkyl, hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl,(1-6C)acyl-, (1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4Calkoxy)carbonyl;

hetAr³ is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

Ar is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted withone or more substituents independently selected from (1-6C)alkyl,halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl,difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino,difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4Ccycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more groups independently selected fromF and (1-3C)alkyl optionally substituted with 1-3 fluoros; AT⁴ is phenyloptionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more groups independently selected from halogen,(1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂;

R^(3a) is halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl,phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl, or a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, O and S and optionally substituted with one or more groupsindependently selected from (1-6C)alkyl and halogen;

R^(4a) is (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl [optionallysubstituted with one or more groups independently selected from(1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy, (1-6Calkyl)OC(═O)—,aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—,HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a 5-6 memberedheteroaryl ring having 1-3 ring heteroatoms independently selected fromN, S and O and optionally substituted with 1-2 substituentsindependently selected from (1-6C)alkyl, hydroxy(1-6C)alkyl,trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂— (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino and(1-3C trifluoroalkoxy(1-3 C)trifluoroalkyl; and R^(5a) is (1-6C)alkyl,trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, phenyl optionally substitutedwith one or more substituents independently selected from halogen and(1-6C)alkyl, or a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, O and S and optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen.

Additional examples of Trk inhibitors can be found in InternationalPublication No. WO 2014078323, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound ofFormula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

Ring B and the NH—C(═X)—NH moiety are in the trans configuration;

R^(a), R^(b), R^(c) and R^(d) are independently selected from H and(1-3C)alkyl,

or R^(o) and R^(d) are independently selected from H and (1-3C)alkyl,and R^(a) and R^(b) together with the atom to which they are attachedform a cyclopropyl ring;

X is O, S, NH, or N—CN;

R¹ is (1-3C alkoxy)(1-6C)alkyl, (trifluoromethoxy)(1-6C)alkyl, (1-3Csulfanyl)(1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, aminocarbonyl(1-6C)alkyl, hydroxy(1-6C)alkyl,dihydroxy(2-6C)alkyl, (1-6C)alkyl, (1-3Calkylamino)(1-3C)alkyl, (1-4Calkoxycarbonyl)(1-6C)alkyl, amino(1-6C)alkyl, hydroxy(1-3Calkoxy)(1-6C)alkyl, di(1-3C alkoxy)(1-6C)alkyl, (1-3Calkoxy)trifluoro(1-6C)alkyl, hydroxytrifluoro(1-6C)alkyl, (1-4Calkoxycarbonyl)(1-3C alkoxy)(1-6C)alkyl or hydroxycarbonyl(1-3Calkoxy)(1-6C)alkyl;

R² is H, F, or OH;

Ring B is Ar¹ or hetAr¹;

Ar¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen, CF₃, CF₃O—, (1-4C)alkoxy,hydroxy(1-4C)alkyl, (1-6C)alkyl and CN; hetAr¹ is a 5-6 memberedheteroaryl having 1-3 ring heteroatoms independently selected from N, Sand O, and optionally substituted with one or more substituentsindependently selected from (1-6C)alkyl, halogen, OH, CF₃, NH₂ andhydroxy(1-2C)alkyl;

Ring C is

R³ is H, (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹,(3-7C)cycloalkyl, hetAr², or a C5-C8 bridged carbocyclic ring;

Ar² is phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O;

hetAr² is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, O and S and optionally substituted withone or more substituents independently selected from (1-6C)alkyl andhalogen;

R⁴ is selected from -6C alkyl)SO₂—, (1-6C alkyl)C(═O)— and from thestructures:

R^(m) is (1-3C)alkyl substituted with 1-3 fluoros, or (3-4C)cycloalkyl;

R^(n) is (1-3C)alkyl;

R⁴ is (1-3C)alkyl optionally substituted with 1-3 fluoros;

R^(x) is (1-6C)alkyl, halogen, CN, hydroxy(1-6C)alkyl,trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6C cycloalkyl)CH₂—, (3-6Ccycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl, (1-6C)alkoxy,(1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6C alkyl)amino,trifluoro(1-3C)alkoxy or trifluoro(1-6C)alkyl;

n is 0, 1, 2, 3 or 4;

m is 0, 1, 2 or 3;

R^(y) is F or (1-3C)alkyl optionally substituted with 1-3 fluoros;

p is 0, 1 or 2;

R^(z) is (3-4C)cycloalkyl, or (1-3C)alkyl optionally substituted with1-3 fluoros; and R⁵ is H, (1-6C)alkyl, monofluoro(1-6C)alkyl,difluoro(1-6C)alkyl, trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl,pentafluoro(2-6C)alkyl, halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl,(1-3C alkoxy)(1-4C)alkyl, (1-4C alkyl)OC(═O)—, (1-6C)alkylsulfanyl,phenyl [optionally substituted with one or more substituentsindependently selected from halogen, (1-6C)alkyl and (1-6C)alkoxy],(3-4C)cycloalkyl, amino, aminocarbonyl, or trifluoro(1-3 C alkyl)amido.

Additional examples of Trk inhibitors can be found in InternationalPublication No. WO 2014078322, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound ofFormula I:

or stereoisomers, tautomers, or pharmaceutically acceptable salts,solvates or prodrugs thereof, wherein:

X is O, S, NH or N—CN;

Ring A is

D is O or S;

R¹ is phenyl optionally substituted with one or more substituentsindependently selected from halogen and (1-3C)alkyl;

R is (1-6C)alkyl [optionally substituted with 1 to 5 fluoros] or(3-6C)cycloalkyl [optionally substituted with one or two fluoros];

Ring C is formula C-1 or C-2

R³ is (1-6C)alkyl, hydroxy(1-6C)alkyl, Ar², hetCyc¹, (3-7C)cycloalkyl,or hetAr²;

Ar is phenyl optionally substituted with one or more groupsindependently selected from halogen and (1-6C)alkyl;

hetCyc¹ is a 5-6-membered saturated or partially unsaturatedheterocyclic ring having 1-2 ring heteroatoms independently selectedfrom N and O; hetAr² is a 5-6 membered heteroaryl ring having 1-3 ringheteroatoms independently selected from N, O and S and optionallysubstituted with one or more groups independently selected from(1-6C)alkyl and halogen;

R⁴ is H, OH, (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluro(2-6C)alkyl, pentafluro(2-6C)alkyl,cyano(1-6C)alkyl, hydroxy(1-6C)alkyl, dihydroxy(2-6C)alkyl, (1-3Calkoxy)(1-6C)alkyl, amino(1-6C)alkyl, aminocarbonyl(1-6C)alkyl,(1-3C)alkylsulfonamido(1-6C)alkyl, sulfamido(1-6C)alkyl,hydroxycarbonyl(1-6C)alkyl, hetAr³(1-6C)alkyl, Ar³(1-6C)alkyl,(1-6C)alkoxy, monofluoro(1-6C)alkoxy, difluoro(1-6C)alkoxy,trifluoro(1-6C)alkoxy, tetrafluoro(2-6C)alkoxy, pentafluoro(2-6C)alkoxy,cyano(1-6C)alkoxy, hydroxy(1-6C)alkoxy, dihydroxy(2-6C)alkoxy,amino(2-6C)alkoxy, hydroxyl-carbonyl(1-6C)alkoxy, hetCyc²(1-6C)alkoxy,hetAr³(1-6C)alkoxy, Ar³(1-6C)alkoxy, (1-4C alkoxy)(1-6C)alkoxy, (1-3Calkylsulfonyl)(1-6C)alkoxy, (3-6C)cycloalkyl [optionally substitutedwith F, OH, (1-6C alkyl), (1-6C) alkoxy, or (1-3C alkoxy)(1-6C)alkyl],hetAr⁴, hetAr⁴—O—, Ar⁴, hetCyc²(O)CH₂—, (1-4Calkoxycarbonyl)(1-6C)alkoxy, hydroxycarbonyl(1-6C)alkoxy,aminocarbonyl(1-6C)alkoxy, hetCyc²C(═O)(1-6C)alkoxy, hydroxy(1-3Calkoxy)(1-6C)alkoxy, hydroxytrifluoro(1-6C)alkoxy, (1-3C)alkylsulfonamido(1-6C)alkoxy, (1-3 C)alkylamido(1-6C)alkoxy, di(1-3Calkyl)amino-carboxy, hetCyc²C(═O)O—, hydroxydifluoro(1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, (1-6C)alkoxycarbonyl, hydroxylcarbonyl,aminocarbonyl, (1-3C alkoxy)aminocarbonyl, hetCyc, halogen, CN,trifluoromethylsulfonyl, N-(1-3C alkyl)oxadiazolonyl, or hetAr⁵;

hetCyc² is a 4-6 membered heterocyclic ring having 1-2 ring heteroatomsindependently selected from N and O and optionally substituted with 1-2groups independently selected from (1-6C)alkyl, (1-4Calkylcarboxy)(1-6C)alkyl, and (1-6C)acyl; hetCyc is a 4-7 memberedheterocycle having 1-2 ring heteroatoms independently selected from Nand O and optionally substituted with one or more substituentsindependently selected from F, CN, (1-6C)alkyl, trifluoro(1-6C)alkyl,hydroxy(1-6C)alkyl, (1-3C alkoxy)(1-6C)alkyl, (1-6C)acyl-,(1-6C)alkylsulfonyl, trifluoromethylsulfonyl and (1-4C alkoxy)carbonyl;

hetAr is a 5-membered heteroaryl ring having 1-3 ring atomsindependently selected from N, O and S and optionally substituted with(1-6C)alkyl;

Ar is phenyl optionally substituted with (1-4C)alkoxy;

hetAr⁴ is a 5-6 membered heteroaryl ring having 1-3 ring heteroatomsindependently selected from N, S and O and optionally substituted withone or more substituents independently selected from (1-6C)alkyl,halogen, CN, hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl,difluoro(1-6C)alkyl, fluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂-(3-6C cycloalkyl)C(O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino, (1-3C trifluoroalkoxy), fluoro(1-6C alkyl)amino,difluoro(1-6C alkyl)amino, trifluoro(1-6C alkyl)amino, and (3-4Ccycloalkyl)amino;

hetAr⁵ is a group selected from the structures:

where R^(z) is (3-4C)cycloalkyl or (1-3C)alkyl (optionally substitutedwith 1-3 fluoros), wherein each of said hetAr⁵ groups is optionallyfurther substituted with one or more groups independently selected fromF and (1-3C)alkyl optionally substituted with 1-3 fluoros;

Ar⁴ is phenyl optionally substituted with one or more groupsindependently selected from (1-6C)alkyl, halogen, CN, CF₃, CF₃O—,(1-6C)alkoxy, (1-6C alkyl)OC(O)—, aminocarbonyl, (1-6C)alkylthio,hydroxy(1-6C)alkyl, (1-6C alkyl)SO₂—, HOC(O)— and (1-3C alkoxy)(1-3Calkyl)OC(═O)—;

R⁵ is (1-6C)alkyl, monofluoro(1-6C)alkyl, difluoro(1-6C)alkyl,trifluoro(1-6C)alkyl, tetrafluoro(2-6C)alkyl, pentafluoro(2-6C)alkyl,halogen, CN, (1-4C)alkoxy, hydroxy(1-4C)alkyl, (1-3C alkoxy)(1-4C)alkyl,(1-4C alkyl)OC(═O)—, (1-6C)alkylthio, (3-4C)cycloalkyl, amino,aminocarbonyl, trifluoro(1-3C alkyl)amido, or phenyl (optionallysubstituted with one or more groups independently selected from halogen,(1-6C)alkyl and (1-6C)alkoxy); or

R⁴ and R⁵ together with the atoms to which they are attached form a 5-6membered saturated, partially unsaturated or unsaturated carbocyclicring optionally substituted with one or more substituents independentlyselected from (1-6C)alkyl, or

R⁴ and R⁵ together with the atoms to which they are attached form 5-6membered saturated, partially unsaturated or unsaturated heterocyclicring having a ring heteroatom selected from N, O or S, wherein saidheterocyclic ring is optionally substituted with one or two substituentsindependently selected from (1-6C alkyl)C(═O)O—, (1-6C)acyl, (1-6C)alkyland oxo, and said sulfur ring atom is optionally oxidized to S(═O) orSO₂; ³a is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moregroups independently selected from (1-6C)alkyl and halogen;

R^(4a) is hydrogen, (1-6C)alkyl, trifluoro(1-6C)alkyl, phenyl[optionally substituted with one or more groups independently selectedfrom (1-6C)alkyl, halogen, CN, CF₃, CF₃O—, (1-6C)alkoxy,(1-6Calkyl)OC(═O)—, aminocarbonyl, (1-6C)alkylthio, hydroxy(1-6C)alkyl,(1-6C alkyl)SO₂—, HOC(═O)— and (1-3C alkoxy)(1-3C alkyl)OC(═O)—], or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, S and O and optionally substituted with 1-2substituents independently selected from (1-6C)alkyl,hydroxy(1-6C)alkyl, trifluoro(1-6C)alkyl, (3-6C)cycloalkyl, (3-6Ccycloalkyl)CH₂— (3-6C cycloalkyl)C(═O)—, (1-3C alkoxy)(1-6C)alkyl,(1-6C)alkoxy, (1-6C)alkylsulfonyl, NH₂, (1-6C alkyl)amino, di(1-6Calkyl)amino and (1-3C trifluoroalkoxy)(1-3C)trifluoroalkyl; and

R^(5a) is hydrogen, halogen, (1-6C)alkyl, trifluoro(1-6C)alkyl,(3-6C)cycloalkyl, phenyl optionally substituted with one or moresubstituents independently selected from halogen and (1-6C)alkyl, or a5-6 membered heteroaryl ring having 1-3 ring heteroatoms independentlyselected from N, O and S and optionally substituted with one or moregroups independently selected from (1-6C)alkyl and halogen.

Further examples of Trk inhibitors can be found in InternationalPublication No. WO 2015175788, which is incorporated by reference in itsentirety herein. For example, a Trk inhibitor can be a compound1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea,or a pharmaceutically acceptable salt thereof. In some embodiments, thecompound is a chloride salt.

Exemplary Trk inhibitors include AR-772, AR-786, AR-256, and AR-618.

Non-limiting examples of Trk inhibitors can be found in U.S. Pat. No.8,299,057 and International Publication No. WO 2009/013126 both of whichare incorporated by reference in their entireties. For example, a Trkinhibitor can be a compound of Formula (I):

wherein:

X is —CH₂—, —CH(OH)—, —CH(OR′)— or —C(R′R″)—, wherein:

R′ is C₁-C₆ alkyl and R″ is hydrogen;

Ar is phenyl, pyrazolyl or pyridyl optionally substituted with one ormore substituents independently selected from halogen, nitro, COR4, OR7,NR5R6, NHSO₂R10, a straight or branched C₁-C6 alkyl optionallysubstituted by a heterocyclyl, in its turn optionally substituted by astraight or branched C₁-C₆ alkyl or an heterocyclylalkyl, or

a heterocyclyl optionally substituted by a straight or branched C₁-C₆alkyl, in its turn optionally substituted by a heterocyclyl or a C₁-C₆alkoxycarbonyl, or a C₁-C₆ dialkylamino:

R4 is NR5R6, or a heterocyclyl, optionally further substituted by astraight or branched C₁-C₆ alkyl, heterocyclylalkyl, heterocyclyl or aC₁-C₆ dialkylamino;

R5 and R6 are independently hydrogen, R8R9N—C₂-C₆ alkyl, R8O—C₂-C₆alkyl,a straight or branched C₁-C₆ alkyl optionally further substituted byC₁-C₆ alkoxy, C₁-C₆ dialkylamino, halogen, phenyl, hydroxyl orheterocyclyl in its turn optionally substituted by alkyl, C₃-C₆cycloalkyl optionally substituted by hydroxyl or trifluoro C₁-C₆ alkyl,heterocyclyl optionally substituted by C₁-C₆ alkyl in its turnoptionally substituted by halogen or heterocyclyl, C₁-C₆alkoxycarbonyl,C₁-C₆ dialkylamino, heterocyclyl, or phenyl,

or R⁵ and R⁶, taken together with the nitrogen atom to which they arebonded, may form a heterocyclyl group optionally substituted by astraight or branched C₁-C₆ alkyl, in its turn optionally substituted bya heterocyclyl or a C₁-C₆ alkoxycarbonyl, a C₁-C₆ dialkylamino or aheterocyclyl;

R⁷ is straight or branched C₁-C₆ alkyl, optionally substituted byC₁-C₆dialkylamino or heterocyclyl in its turn substituted by C₁-C₆alkyl;

R8 and R9 are independently an optionally further substituted straightor branched C₁-C₆ alkyl;

R10 is an optionally further substituted straight or branched C₁-C₆alkyl;

R is phenyl or pyridyl optionally substituted halogen or straight orbranched C₁-C₆ alkyl;

R1, R2 and R3 are hydrogen;

or optical isomers, tautomers or pharmaceutically acceptable saltthereof.

For example, a Trk inhibitor can be entrectinib(N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methyl-piperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide),or a pharmaceutically acceptable salt thereof. For example, a Trkinhibitor can be a polymorph such as those described in U.S. PublicationNo. 2015/0051222 or International Publication No. WO 2013/174876, bothof which are incorporated by reference in their entireties herein. Insome embodiments, a Trk inhibitor can be any disclosed in U.S.Publication No. 2015/0283132, International Publication No. WO2015/124697, U.S. Pat. No. 8,946,226, International Publication No. WO2010/012733, U.S. Pat. No. 8,912,194, and International Publication No.WO 2010/058006, all of which are incorporated by reference in theirentireties herein.

Additional examples of Trk inhibitors can be found in U.S. PublicationNo. International Publication No. WO 2015/017533, which is incorporatedby reference in its entirety herein.

Further examples of Trk inhibitors can be found in U.S. Publication No.2016/0272725 and International Publication No. WO 2015/112806, both ofwhich are incorporated by reference in their entirety herein. Forexample, a Trk inhibitor can be a compound of Formula (I-A):

or a pharmaceutically acceptable salt thereof,wherein

Ring A′ and Ring B′ are each independently a monocyclic or bicyclic arylor heteroaryl; wherein one of Ring A′ and Ring B′ is a monocyclic arylor heteroaryl and the other is a bicyclic heteroaryl; and at least oneof Ring A′ and Ring B′ comprises at least one nitrogen ring member;

each L¹ and L² is independently —C(R^(1′))(R^(2′))—, —O—, —N(R^(k′))—,—S—, —S(O)— or —S(O)₂; each R¹ and R² are independently H, deuterium,halogen, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclicheteroaryl, —OR^(a′), —OC(O)R^(a′), —OC(O)NR^(a′)R^(b′), —OS(O)R^(a′),—OS(O)₂R^(a′), —SR^(a′), —S(O)R^(a′), —S(O)₂R^(a′), —S(O)NR^(a′)R^(b′),—S(O)₂NR^(a′) R^(b′), —OS(O)NR^(a′)R^(b′), —OS(O)₂NR^(a′)R^(b′),—NR^(a′)R^(b+), —NR^(a′)C(O)R^(b′), —NR^(a′)C(O)OR^(b′),—NR^(a′)C(O)NR^(a′)R^(b′), —NR^(a′)S(O)R^(b′), —NR^(a′)S(O)₂R^(b′),—NR^(a′)S(O)NR^(a′)R^(b′), —NR^(a′)S(O)₂NR^(a′)R^(b′), —C(O)R^(a′),—C(O)OR^(a′), —C(O)NR^(a′)R^(b′), —PR^(a′)R^(b′), —P(O)R^(a′)R^(b′),—P(O)₂R^(a′)R^(b′), —P(O)NR^(a′)R^(b′), —P(O)₂NR^(a′)R^(b′),—P(O)OR^(a′), —P(O)₂OR^(a′), —CN, or —NO₂, or R^(1′) and R^(2′) takentogether with the carbon or carbons to which they are attached form aC₃₋₆cycloalkyl or a 4- to 6-membered heterocycloalkyl, wherein eachhydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3-to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, mono- or bicyclicheteroaryl, 4- to 6-membered heterocycloalkyl is independentlyoptionally substituted by deuterium, halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,—OR^(e′), —OC(O)R^(e′), —OC(O)NR^(e′)R^(f′), —OS(O)R^(e′),—OS(O)₂R^(e′), —OS(O)NR^(e′)R^(f′), —OS(O)₂NR^(e)R^(f), —SR^(e′),—S(O)R^(e′), S(O)₂R^(e′), —S(O)NR^(e′)R^(f′), —S(O)₂NR^(e′)R^(f′),—NR^(e′)R^(f′), —NR^(e′)C(O)R^(f′), —NR^(e′)C(O)OR^(f′),NR^(e′)C(O)NR^(e′)R^(f′), —NR^(e′)S(O)R^(f′), —NR^(e′)S(O)₂R^(f′),—NR^(e′)S(O)NR^(e′)R^(f′), —NR^(e′)S(O)₂NR^(e′)R^(f′), —C(O)R^(e″),—C(O)OR^(e′), —C(O)NR^(e′)R^(f′), —PR^(e′)R^(f′), —P(O)R^(e′)R^(f′),—P(O)₂R^(e′)R^(f′), —P(O)NR^(e′)R^(f′), —P(O)₂NR^(e′)R^(f′),—P(O)OR^(e′), —P(O)₂OR^(e′), —CN, or —NO₂;

each R^(k′) is independently H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀aryl, or mono- or bicyclic heteroaryl, wherein each hydrogen atom inC₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, —Or^(e′), —OC(O)R^(e′), —OC(O)NR^(e′)R^(f′),—OS(O)R^(e′), —OS(O)₂R^(e′), —OS(O)NR^(e′)R^(f′), —OS(O)₂NR^(e′)R^(f′),—SR^(e′), —S(O)R^(e′), S(O)₂R^(e′), —S(O)NR^(e′)R^(f′), —S(O)₂NR^(e′R)f,—NR^(e′)R^(f′), —NR^(e′)C(O)R^(f′), —NR^(e′)C(O)OR^(f′),—NR^(e′)C(O)NR^(e′)R^(f′), —NR^(e′)S(O)R^(f′), —NR^(e′)S(O)₂R^(f′),—NR^(e′)S(O)NR^(e′)R^(f′), —NR^(e′)S(O)₂NR^(e′)R^(f′), —C(O)R^(e′),—C(O)OR^(e′), —C(O)NR^(e′)R^(f′), —PR^(e′)R^(f′), —P(O)R^(e′)R^(f′),—P(O)₂R^(e′)R^(f′), —P(O)NR^(e′)R^(f′), —P(O)₂NR^(e′)R^(f′),—P(O)OR^(e′), —P(O)₂OR^(e′), —CN, or —NO₂;

each R^(3′) and R^(4′) is independently deuterium, halogen, —OR^(c′),—OC(O)R^(c′), —OC(O)NR^(c′)R^(d′), —OC(═N)NR^(c′)R^(d′), —OS(O)R^(c′),—OS(O)₂R^(c′), —OS(O)NR^(c′)R^(d′), —OS(O)₂NR^(c′)R^(d′), SR^(c′),—S(O)R^(c′), —S(O)₂R^(c′), —S(O)NR^(c′)R^(d′), —S(O)₂NR^(c′)R^(d′),—NR^(c′)R^(d′), —NR^(c′)C(O)R^(d′), —NR^(c′)C(O)OR^(d′),—NR^(c′)C(O)NR^(c′)R^(d′), —NR^(c′)C(═N)NR^(c′)R^(d′),—NR^(c′)S(O)R^(d′), —NR^(c′)S(O)₂R^(d′), —NR^(c′)S(O)NR^(c′)R^(d′),—NR^(c′)S(O)₂NR^(c′)R^(d′), —C(O)R^(c′), —C(O)OR^(c′),—C(O)NR^(c′)R^(d′), —C(═N)NR^(c′)R^(d′), —PR^(c′)R^(d′),—P(O)R^(c′)R^(d′), —P(O)₂R^(c′)R^(d′), —P(O)NR^(c′)R^(d′),—P(O)₂NR^(c′)R^(d′), —P(O)OR^(c′), —P(O)₂OR^(c′), —CN, —NO₂, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl, or anytwo R^(3′) groups or any two R^(4′) groups taken together with the ringto which they are attached form a C₅₋₈cycloalkyl or a 5- to 8-memberedheterocycloalkyl, wherein each hydrogen atom in C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀aryl, mono- or bicyclic heteroaryl C₅₋₈cycloalkyl or a 5- to 8-memberedheterocycloalkyl is independently optionally substituted by deuterium,halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, —OR^(e′), —OC(O)R^(e′),—OC(O)NR^(e′)R^(f′), —OS(O)R^(e′), —OS(O)₂R^(e′)—OS(O)NR^(e′)R^(f′),—OS(O)₂NR^(e′)R^(f′), —SR^(e′), —S(O)R^(e′), —S(O)₂R^(e′),—S(O)NR^(e′)R^(f′), —S(O)₂NR^(e′)R^(f′), —NR^(e′)R^(f′),—NR^(e′)C(O)R^(f′), —NR^(e′)C(O)OR^(f′), —NR^(e′)C(O)NR^(e′)R^(f′),—NR^(e′)S(O)R^(f′), —NR^(e′)S(O)₂R^(f′), —NR^(e′)S(O)NR^(e′)R^(f′),—NR^(e′)S(O)₂NR^(e′)R^(f′), —C(O)R^(e′), —C(O)OR^(e′),—C(O)NR^(e′)R^(f′), —PR^(e′)R^(f′), —P(O)R^(e′)R^(f′),—P(O)₂R^(e′)R^(f′), —P(O)NR^(e′)R^(f′), —P(O)₂NR^(e′)R^(f′),—P(O)OR^(e′), —P(O)₂OR^(e′), —CN, or —NO₂;

R^(7′) is H, deuterium, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₃₋₆cycloalkyl, 3- to 7-membered heterocycloalkyl, C₆₋₁₀ aryl, or mono-or bicyclic heteroaryl, wherein each hydrogen atom in C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, or mono- or bicyclic heteroaryl isindependently optionally substituted by deuterium, halogen, —OR^(i′),—OC(O)R^(i′), —OC(O)NR^(i′)R^(j′), —OS(O)R^(i′), —OS(O)₂R^(i′),—OS(O)NR^(i′)R^(j′), —OS(O)₂NR^(i′)R^(j′), —SR^(i′), —S(O)R^(i′),—S(O)₂R^(i′), —S(O)NR^(i′)R^(j′), —S(O)₂NR^(i′)R^(j′), —NR^(i′)R^(j′),—NR^(i′)C(O)R^(j′), —NR^(i′)C(O)OR^(j′), —NR^(i′)C(O)NR^(i′)R^(j′),—NR^(i′)S(O)R^(j′), —NR^(i′)S(O)₂R^(j′), —NR^(i′)S(O)NR^(i′)R^(j′),—NR^(i′)S(O)₂NR^(i′)R^(j′), —C(O)R^(i′), —C(O)OR^(i′),—C(O)NR^(i′)R^(j′), —PR^(i′)R^(j′), —P(O)R^(i′)R^(j′),—P(O)₂R^(i′)R^(j′), —P(O)NR^(i′)R^(j′), —P(O)₂NR^(i′)R^(j′),—P(O)OR^(i′), —P(O)₂OR^(i′), —CN, or —NO₂;

each R^(a′), R^(b′), R^(c′), R^(d′), R^(e′), R^(f′), R^(i′) and R^(j′)is independently selected from the group consisting of H, deuterium,C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, C₃₋₆cycloalkyl, 3- to 7-memberedheterocycloalkyl, C₆₋₁₀ aryl, and heteroaryl;

m′ is 2, 3, 4, or 5;

n′ is 2, 3, or 4;

p′ is 0, 1, 2, 3, or 4; and

q′ is 0, 1, 2, 3, or 4; or a pharmaceutically acceptable salt thereof.Exemplary Trk inhibitors include TPX-0005.

A Trk inhibitor can be one found in U.S. Pat. No. 9,187,489 andInternational Publication No. WO 2013/183578, both of which areincorporated by reference in their entireties herein. Exemplary Trkinhibitors include PLX7486 and DS-6051.

Non-limiting examples of Trk inhibitors can be found in U.S. PublicationNo. 2015/0306086 and International Publication No. WO 2013/074518, bothof which are incorporated by reference in their entireties herein.Exemplary Trk inhibitors include TSR-011.

Further examples of Trk inhibitors can be found in U.S. Pat. No.8,637,516, International Publication No. WO 2012/034091, U.S. Pat. No.9,102,671, International Publication No. WO 2012/116217, U.S.Publication No. 2010/0297115, International Publication No. WO2009/053442, U.S. Pat. No. 8,642,035, International Publication No. WO2009092049, U.S. Pat. No. 8,691,221, International Publication No.WO2006131952, all of which are incorporated by reference in theirentireties herein. Exemplary Trk inhibitors include GNF-4256, describedin Cancer Chemother. Pharmacol. 75(1):131-141, 2015; and GNF-5837(N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-yl]amino]-4-methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]-urea),described in ACS Med. Chem. Lett. 3(2): 140-145, 2012, each of which isincorporated by reference in its entirety herein.

Additional examples of Trk inhibitors include those disclosed in U.S.Publication No. 2010/0152219, U.S. Pat. No. 8,114,989, and InternationalPublication No. WO 2006/123113, all of which are incorporated byreference in their entireties herein. Exemplary Trk inhibitors includeAZ623, described in Cancer 117(6):1321-1391, 2011; AZD6918, described inCancer Biol. Ther. 16(3):477-483, 2015; AZ64, described in CancerChemother. Pharmacol. 70:477-486, 2012; AZ-23((S)-5-Chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine),described in Mol. Cancer Ther. 8:1818-1827, 2009; and AZD7451; each ofwhich is incorporated by reference in its entirety.

A Trk inhibitor can include those described in U.S. Pat. Nos. 7,615,383;7,384,632; 6,153,189; 6,027,927; 6,025,166; 5,910,574; 5,877,016; and5,844,092, each of which is incorporated by reference in its entirety.

Further examples of Trk inhibitors include CEP-751, described in Int. J.Cancer 72:672-679, 1997; CT327, described in Acta Derm. Venereol.95:542-548, 2015; compounds described in International Publication No.WO 2012/034095; compounds described in U.S. Pat. No. 8,673,347 andInternational Publication No. WO 2007/022999; compounds described inU.S. Pat. No. 8,338,417; compounds described in InternationalPublication No. WO 2016/027754; compounds described in U.S. Pat. No.9,242,977; compounds described in U.S. Publication No. 2016/0000783;sunitinib(N-(2-diethylaminoethyl)-5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide),as described in PLoS One 9:e95628, 2014; compounds described inInternational Publication No. WO 2011/133637; compounds described inU.S. Pat. No. 8,637,256; compounds described in Expert. Opin. Ther. Pat.24(7):731-744, 2014; compounds described in Expert Opin. Ther. Pat.19(3):305-319, 2009; (R)-2-phenylpyrrolidine substitutedimadizopyridazines, e.g.,(4-((5-chloro-4-(methylamino)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-3-methoxyphenyl)(morpholino)methanoneas described in ACS Med. Chem. Lett. 6(5):562-567, 2015; GTx-186 andothers, as described in PLoS One 8(12):e83380, 2013; K252a((9S-(9α,10β,12α))-2,3,9,10,11,12-hexahydro-10-hydroxy-10-(methoxycarbonyl)-9-methyl-9,12-epoxy-1H-diindolo[12,3-fg:3′,2′,1′-kl]pyrrolo[3,4-i][1,6]benzodiazocin-1-one),as described in Mol. Cell Biochem. 339(1-2):201-213, 2010;4-aminopyrazolylpyrimidines, e.g., AZ-23(((S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-2,4-diamine)),as described in J. Med. Chem. 51(15):4672-4684, 2008; PHA-739358(danusertib), as described in Mol. Cancer Ther. 6:3158, 2007; Gö 6976(5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile),as described in J. Neurochem. 72:919-924, 1999; GW441756((3Z)-3-[(1-methylindol-3-yl)methylidene]-1H-pyrrolo[3,2-b]pyridin-2-one),as described in IJAE 115:117, 2010; milciclib (PHA-848125AC), describedin J. Carcinog. 12:22, 2013; AG-879((2E)-3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-cyano-2-propenethioamide);altiratinib(N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);cabozantinib(N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);lestaurtinib ((5S,6S,8R)-6-Hydroxy-6-(hydroxymethyl)-5-methyl-7,8,14,15-tetrahydro-5H-16-oxa-4b,8a,14-triaza-5,8-methanodibenzo[b,h]cycloocta[jkl]cyclopenta[e]-as-indacen-13(6H)-one);dovatinib(4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-onemono 2-hydroxypropanoate hydrate); sitravatinib(N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);ONO-5390556; regorafenib(4-[4-({[4-Chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamidehydrate); VSR-902A; all of the references above are incorporated byreference in their entireties herein.

In some embodiments, a Trk inhibitor is selected from the groupconsisting of:

-   (6R)-9-fluoro-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1^(7,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;-   (6R)-12-oxa-2,16,20,21,24,26-hexaazapentacyclo[16.5.2.1^(7,11).0^(2,6).0^(21,25)]hexacosa-1(24),7(26),8,10,18(25),    19,22-heptaen-17-one;-   (6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]    hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R,13S)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.1^(7,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;-   (6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0^(2,6).0^(7,12).0^(22,26)]    hexacosa-1 (25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R,13R)-9-fluoro-13-hydroxy-2,11,15,19,20,23-hexaazapentacyclo-[15.5.2.1^(7,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;-   (6R)-9-fluoro-13-oxa-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;-   (6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0^(2,6).0^(7,12).0^(23,27)]heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;-   (6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.1^(7,11).0^(2,6).0^(21,25)]hexacosa-1(24),7,9,18(25),19,22-hexaene-17,26-dione;-   (6R)-9-fluoro-2,11,13,16,20,21,24-heptaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;-   (6R)-9-fluoro-2,11,13,17,21,22,25-heptaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-13,16-dioxa-2,11,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]-pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;-   (6R)-9-fluoro-14-oxa-2,11,18,19,22-pentaazapentacyclo[14.5.2.1^(7,11).0^(2,6).0^(19,23)]tetracosa-1(22),7,9,16(23),    17,20-hexaene-15,24-dione;-   (6R)-9-fluoro-13,16-dioxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R,13R)-9,13-difluoro-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1^(7,11).0^(2,6).0^(20,24)]pentacosa-1(23),    7,9,17(24), 18,21-hexaene-16,25-dione;-   (6R)-9-fluoro-17-methyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),    7,9,11,18(25), 19,22-heptaene;-   1-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-16-yl]ethan-1-one;-   1-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1    (24),7,9,11,18(25), 19,22-heptaen-16-yl]-2-hydroxyethan-1-one;-   (6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),    7,9,11,19(26),20,23-heptaene;-   (6R)-9-fluoro-16-methanesulfonyl-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]    pentacosa-1 (24),7,9,11,18(25), 19,22-heptaene;-   2-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-16-yl]acetic    acid;-   (6R)-9-fluoro-17-methanesulfonyl-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]    hexacosa-1(25),7,9,11,19(26),20,23-heptaene;-   (6R)—N-ethyl-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).    0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaene-17-carboxamide;-   (6R)—N-ethyl-9-fluoro-13-oxa-2,16,20,2,24-pentaazapentacyclo-[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaene-16-carboxamide;-   (6S)-9-fluoro-4,13-dioxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaene-3,18-dione;-   (6S)-9-fluoro-4,13-dioxa-2,11,16,20,21,24-hexaazapentacyclo    [16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7(12),8,10,18(25),    19,22-heptaene-3,17-dione;-   (6R)-9-fluoro-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),    7,9,11,18(25), 19,22-heptaen-17-one;-   (6R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),    7,9,11,18(25), 19,22-heptaen-17-one;-   (6R,13R)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.1^(7,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),    18,21-hexaene-16,25-dione;-   (6R,13S)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo    [15.5.2.1^(7,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),    18,21-hexaene-16,25-dione;-   (6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo    [17.5.2.0^(2,6).0^(7,12).0^(22,26)]    hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-15,15-dimethyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),    7,9,11,18(25), 19,22-heptaen-17-one;-   (6R)-9-fluoro-13-oxa-2,11,16,17,21,25,26,29-octaazahexacyclo[21.5.2.0^(2,6).0^(7,12).0^(16,20).0^(26,30)]triaconta-1    (29),7,9,11,17,19,23(30),24,27-nonaen-22-one;-   (6R)-9-fluoro-13-oxa-2,11,19,21,25,26,29-heptaazahexacyclo[21.5.2.0^(2,6).0^(7,12).0^(15,20).0^(26,30)]triaconta-1(29),7,9,11,15(20),16,18,23(30),24,27-decaen-22-one;-   (6R)-9-fluoro-13,13-dimethyl-2,11,15,19,20,23-hexaazapentacyclo    [15.5.2.1^(7,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;-   (4R,6R,15S)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo    [17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;-   (4R,6S,15    S)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo    [17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;-   (4R,6R)-9-fluoro-4-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo    [17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;-   (4R,6S)-9-fluoro-4-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo    [17.5.2.0^(2,6).0^(7,12).0^(22,26)]    hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;-   (4R,6R)-9-fluoro-4-hydroxy-13-oxa-2,16,20,21,24-pentaazapentacyclo    [16.5.2.0^(2,6).0^(7,12).0^(21,25)] pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;-   (4R,6S)-9-fluoro-4-hydroxy-13-oxa-2,16,20,21,24-pentaazapentacyclo    [16.5.2.0^(2,6).0^(7,12).0^(21,25)] pentacosa-1 (24),7,9,11,18(25),    19,22-heptaen-17-one;-   (4R,6R,15R)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo    [17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;-   (4R,6S,15R)-9-fluoro-4,15-dihydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo    [17.5.2.0^(2,6).0⁷′1².0^(22,26)]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;    and-   (15S)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1    (25),7(12),8,10,19(26),20,23-heptaen-18-one, or a pharmaceutically    acceptable salt thereof.

In some embodiments, a Trk inhibitor is selected from the groupconsisting of:

-   (R)—N-tert-butyl-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(3-methylpyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((5-methylfuran-2-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-methyl-1-morpholinopropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidine-4-carboxylic    acid;-   (R)-2-(1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carbonyl)piperidin-4-yl)acetic    acid;-   (R)—N-cyclopropyl-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclobutyl-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-((2S)-bicyclo[2.2.1]heptan-2-yl)-5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-hydroxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)((S)-3-hydroxypyrrolidin-1-yl)methanone;-   (5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)((R)-3-hydroxypyrrolidin-1-yl)methanone;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((1-methyl-1H-imidazol-4-yl)methyl)    pyrazole[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((1-methyl-1H-pyrazol-4-yl)methyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(1-methyl-1H-imidazol-5-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(2-oxoimidazolidin-1-yl)ethyl)    pyrazole[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-(1H-imidazol-4-yl)ethyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazole    [1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((R)-2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N,N-dimethylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-(1H-imidazol-1-yl)ethyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-2,3-dihydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxyazetidin-1-yl)methanone;-   (R)-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone;-   Trans-4-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexanecarboxylic    acid;-   5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(3-fluorophenyl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-tert-butyl-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-cyanopropan-2-yl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(cyanomethyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-fluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-cyclopropyl-5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-tert-butyl-5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R,4R)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-(methyl    sulfonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1-sulfamoylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(methylsulfonamido)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-sulfamoylethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)-N-(2-hydroxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(4-hydroxy-4-methyl    cyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (Diastereomer 1);-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(4-hydroxy-4-methylcyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide    (Diasteromer 2);-   (R)—N-cyclopropyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-tert-butyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)-N-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((S)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((R)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-methyl-1-(methylsulfonamido)propan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-amino-2-methylpropyl)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-tert-butyl-5-(4,4-difluoro-2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1,3-dihydroxy-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((3    S,4R)-3-fluoropiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((S)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)    pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((R)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-(trifluoromethyl)phenyl)    pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-cyanopropan-2-yl)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(1-fluoro-2-methylpropan-2-yl)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   ((R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(3-fluoro-5-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazole    [1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(3-fluoro-5-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-tert-butyl-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(1-fluoro-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-1-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclopropanecarboxylic    acid;-   (R)—N-cyclopropyl-5-(2-(3-fluoro-5-(2-morpholinoethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-(2-morpholinoethoxy) phenyl)    pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(5-fluoro-2-(2-morpholinoethoxy)phenyl)    pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-2,3-dihydroxypropoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-(2-methoxyethoxy)phenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(5-fluoro-2-(2-methoxyethoxy)phenyl)    pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(pyrrolidin-1-yl)methanone;-   (R)—N-(5-fluoropyridin-2-yl)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-methoxyazetidin-1-yl)methanone;-   N-(3-chloro-2-fluoropropyl)-5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-(trifluoromethyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((cis)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclobutyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclobutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((1S,2S)-2-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((1S,2R)-2-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((1 S,3    S)-3-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(cyclopropylmethyl)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxyazetidin-1-yl)methanone;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((S)-2-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((R)-2-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-(1-cyclopropylethyl)-5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((R)-1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((S)-1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methoxypropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxy-3-methoxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((trans)-2-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((S)-1-hydroxy-3-methylbutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((R)-1-hydroxy-3-methylbutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((R)-1-cyclopropylethyl)-5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((S)-1-cyclopropylethyl)-5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-azetidin-1-yl(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methanone;-   (R)-(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-(hydroxymethyl)azetidin-1-yl)methanone;-   (5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)((S)-3-hydroxypyrrolidin-1-yl)methanone;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((R)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(2,2,2-trifluoroethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-hydroxy-2-methylpropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((1R,2R)-2-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2,2-difluoroethyl)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((1R,2S)-2-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((1R,2R)-2-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-(5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(piperidin-1-yl)methanone;-   5-((R)-2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((2R,3    S,4S)-3-(hydroxymethyl)bicyclo[2.2.1]heptan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-(5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxyazetidin-1-yl)methanone;-   5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-tert-butyl    3-(5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)propylcarbamate;-   (R)—N-(3-aminopropyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((S)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((S)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((R)-3-chloro-2-hydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-chloroethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-(5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxy-3-methylazetidin-1-yl)methanone;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(3-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-(2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((R)-2,3-dihydroxypropyl)-5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(4-hydroxybutyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-tert-butoxyethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-((1 S,3    S)-3-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N—((S)-2-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N—((R)-2-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(1,3-dihydroxypropan-2-yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(6-oxo-1,6-dihydropyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(1-(methylsulfonyl)piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-chloroethyl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-bromoethoxy)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(3-hydroxy-2,2-dimethylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((1 S,3    S)-3-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(4-hydroxypiperidin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-(4-methylpiperazin-1-yl)ethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(2-methoxyethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(1,3-dihydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((2S,3R)-1,3-dihydroxybutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((2S,3    S)-1,3-dihydroxybutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-((2R,3    S)-1,3-dihydroxybutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-1-hydroxypropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-1-hydroxybutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-1-hydroxy-3-methylbutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N—((S)-1-hydroxy-3,3-dimethylbutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-cyclopropyl-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-cyclopropyl-5-(2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-tert-butyl-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclobutyl-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N—((R)-2-hydroxypropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N-(2-methoxyethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-(5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(3-hydroxyazetidin-1-yl)methanone;-   (R)-5-(2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N-(1-(hydroxymethyl)cyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N-((cis)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N-((1    S,3S)-3-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N-((1R,2R)-2-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-2-methylpyridin-3-yl)pyrrolidin-1-yl)-N—((R)-quinuclidin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-((1 S,3    S)-3-hydroxycyclopentyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2-ethyl-5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxy-2-methylpropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-tert-butyl-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-chloroethyl)-5-(2-(5-fluoro-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-cyclopropyl-5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R)-2-(2-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-cyclopropyl-5-((2R)-2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R)-2-(3-((2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-cyclopropyl-5-((2R)-2-(3-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R)-2-(3-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N-cyclopropyl-5-((2R)-2-(2-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R)-2-(2-(2,3-dihydroxypropoxy)-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R,5S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)-N—((R)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R,5    S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R,5    S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R,5    S)-2-(5-fluoropyridin-3-yl)-5-(hydroxymethyl)pyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2R,4S)-2-(3-fluorophenyl)-4-hydroxypyrrolidin-1-yl)-N-methylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((2S,5R)-5-(5-fluoropyridin-3-yl)-2-(hydroxymethyl)-2-methylpyrrolidin-1-yl)-N—((S)-1,1,1-trifluoropropan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-(5-(2-(2-amino-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)(azetidin-1-yl)methanone;-   (R)-tert-butyl    3-(5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamido)propylcarbamate;-   (R)—N-(3-aminopropyl)-5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(2-tert-butoxyethoxy)-5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(2-chloro-5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(2-hydroxyethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-tert-butyl-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-isopropylpyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-(6-methylpyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclobutyl-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(cyclopropylmethyl)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N—((S)-1-hydroxy-3,3-dimethylbutan-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-((1R,2R)-2-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((R)-1-cyclopropylethyl)-5-((R)-2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   N—((S)-1-cyclopropylethyl)-5-((R)-2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   5-((R)-2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-((trans)-4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-1-methyl-2-oxo-1,2-dihydropyridin-3-yl)pyrrolidin-1-yl)-N-(5-fluoropyridin-2-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(3-methyl-1H-pyrazol-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(1-methyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(3-cyclopropyl-1H-pyrazol-5-yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-(3-ethyl-1H-pyrazol-5-yl)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;    and-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-(1-isopropyl-1H-pyrazol-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide,    or a pharmaceutically acceptable salt thereof.-   In some embodiments, a Trk inhibitor is selected from the group    consisting of:-   5-fluoro-2-[[(1    S)-1-(5-fluoro-2-pyridyl)ethyl]amino]-6-[(5-isopropoxy-1H-pyrazol-3-yl)amino]pyridine-3-carbonitrile;    ((2E)-3-[3,5-Bis(1,1-dimethylethyl)-4-hydroxyphenyl]-2-cyano-2-propenethioamide);-   2,2-dichloro-N-[3-[(7-chloroquinolin-4-yl)amino]propyl]-N-methylacetamide;-   N-[3-[[2,3-dihydro-2-oxo-3-(1H-pyrrol-2-ylmethylene)-1H-indol-6-yl]amino]-4-methylphenyl]-N′-[2-fluoro-5-(trifluoromethyl)phenyl]-urea;-   (S)-5-chloro-N2-(1-(5-fluoropyridin-2-yl)ethyl)-N4-(5-isopropoxy-1H-pyrazol-3-yl)pyrimidine-(S)—N-(1-(5-fluoropyrimidin-2-yl)ethyl)-3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine,4-diamine;-   5,6,7,13-tetrahydro-13-methyl-5-oxo-12H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-12-propanenitrile;-   1,3-dihydro-3-[(1-methyl-1H-indol-3-yl)methylene]-2H-pyrrolo[3,2-b]pyridin-2-one;-   or a pharmaceutically acceptable salt thereof.-   In some embodiments, a Trk inhibitor is selected from the group    consisting of:-   (2R)-2-({4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-5-fluoropyrimidin-2-yl}amino)-2-(4-fluorophenyl)ethanol;-   5-bromo-N⁴-(3-cyclopropyl-1H-pyrazol-5-yl)-N²-[(1    S)-1-(4-fluorophenyl)ethyl]pyrimidine-2,4-diamine;-   (2R)-2-({5-chloro-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-2-(4-fluorophenyl)ethanol;-   (2R)-2-({5-chloro-4-[(3-isopropoxy-1H-pyrazol-5-yl)amino]pyrimidin-2-yl}amino)-2-(4-fluorophenyl)ethanol;-   (3    S)-3-({5-chloro-4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl}amino)-3-(4-fluorophenyl)-N-methylpropanamide;-   2-({5-chloro-2-{[(1    S)-1-(4-fluorophenyl)ethyl]amino}-6-[(5-isopropoxy-1H-pyrazol-3-yl)amino]pyrimidin-4-yl}amino)propane-1,3-diol;-   2-[(5-chloro-6-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]-2-{[(1S)-1-(4-fluorophenyl)ethyl]amino]pyrimidin-4-yl)amino}propane-1,3-diol;-   5-chloro-N⁴-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-[(1    S)-(4-fluoro-phenyl)-ethyl]-6-(4-methyl-piperazin-1-yl)-pyrimidine-2,4-diamine;-   (2R)-2-({4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-7-fluoroquinazolin-2-yl}amino)-2-(4-fluorophenyl)ethanol;    and-   2-[(5-chloro-6-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]-2-{[(1R)-1-(4-fluorophenyl)-2-hydroxyethyl]amino}pyrimidin-4-yl)amino]propane-1,3-diol;

or a pharmaceutically acceptable salt thereof.

In some embodiments, a Trk inhibitor is selected from the groupconsisting of

-   1-(3-tert-butyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-tert-butyl-1-p-tolyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea    hydrochloride;-   trans-1-(4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   trans-1-(4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-tert-butyl-1-methyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(1,3-dimethyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-tert-butyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-tert-butyl-1-(4-fluorophenyl)-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-cyclopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(1,3-diphenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-isopropyl-1-phenyl-H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-tert-butyl-1-(3-fluorophenyl)-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-(pyridin-3-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-1H-pyrazol-5-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)thiourea;-   1-(2-(3-fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(2-(4-fluorophenyl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-cyclopentyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(1-ethyl-3-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-methyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(1,3-dimethyl-4-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-tert-butyl-1-o-tolyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-tert-butyl-1-m-tolyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-4-phenyl-1H-pyrazol-5-yl)urea;-   1-(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-(1-methyl-1H-pyrazol-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(3-tert-butyl-1-(tetrahyro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-(pyridin-2-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(6,6-dimethyl-2-phenyl-2,4,5,6-tetrahydro-yclopenta    [c]pyrazol-3-yl)-3-(trans-1-(2-methoxyethyl)-4-phenyl-pyrrolidin-3-yl)urea;-   1-(7,7-dimethyl-2-phenyl-4,5,6,7-tetrahydro-2H-indazol-3-yl)-3-(trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-(pyridin-4-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   trans-1-(4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   trans-1-(-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea;-   trans-1-(4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea;-   trans-1-(4-(3-chlorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea;-   trans-1-(4-(2-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea;-   trans-1-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)-3-(1-(2-methoxyethyl)-4-(thiophen-2-yl)pyrrolidin-3-yl)urea;-   1-((3,4-trans)-4-(2,4-dimethylthiazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(trans-1-(2-methoxyethyl)-4-(oxazol-5-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(trans-4-(isoxazol-5-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3,4-trans)-1-(2-methoxyethyl)-4-(3-methoxyphenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(1-(2-methoxyethyl)-4-(thiazol-2-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(1,3-diphenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)urea;-   1-(1,4-dimethyl-3-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-cyclopropyl-1-methyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1,1′-dimethyl-1H,    1′H-3,4′-bipyrazol-5-yl)urea;-   1-(3-(3-cyanophenyl)-1-methyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-(4-cyanophenyl)-1-methyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(imidazo[1,2-a]pyridin-5-yl)-1-methyl-1H-pyrazol-5-yl)urea;-   1-(4-chloro-1,3-diphenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1,3-diphenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1,3-dimethyl-4-phenyl-1H-pyrazol-5-yl)urea;-   1-(4-cyano-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1-methyl-3-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1-methyl-3-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-cyano-3-(cyanomethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethyl-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-methyl-1-phenyl-1H,    1′H-3,4′-bipyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(oxetan-3-ylmethoxy)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((3-methyloxetan-3-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   tert-butyl 3-(3-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)ureido)-2-phenyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5(2H)-carboxylate;-   1-(3-isopropyl-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-isopropyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H-furo[3,4-c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-(1-hydroxy-2-methylpropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(5-oxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(thiophen-2-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(3-(methoxymethyl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(3-(methoxymethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-p-tolyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-m-tolyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-o-tolyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)urea;-   1-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(3-(4-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(2,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(3-(1-hydroxy-2-methylpropan-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(1-hydroxy-2-methylpropan-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-(4-chlorophenyl)-1-methyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(2,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-fluorophenyl)-1-methyl-1H-pyrazol-5-yl)urea;-   methyl 4-(5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(2-hydroxyethyl)-3-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(methoxymethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(methoxymethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(4-(methylthio)phenyl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1,3-diphenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-methoxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-(2-methoxyethoxy)phenyl)-1-methyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methoxy-3-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(hydroxymethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-(benzyloxy)-1-methyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   trans-1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-(cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3 S,4R)-4-(3,4-difluoro-phenyl)-1-(2-methoxyethyl)    pyrrolidin-3-yl)-3-(3-(4-methoxybenzyloxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-fluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxy-2-methylpropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(2-cyclohexyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-(pyridin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(5-methylpyrazin-2-yl)-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1,4-dimethyl-3-(5-methylpyrazin-2-yl)-1H-pyrazol-5-yl)urea;-   ethyl    5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carboxylate;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(pyrazin-2-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-methyl-4-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-1-methyl-4-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)urea    dihydrochloride;-   1-(5-acetyl-2-phenyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-(hydroxymethyl)-3-(methoxymethyl)-1-phenyl-1H-pyrazol-5-yl)urea;-   4-(5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoic    acid;-   4-(5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzamide;-   4-(5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)-N-methylbenzamide;-   4-(5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)-N,N-dimethylbenzamide;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-(hydroxymethyl)phenyl)-1-methyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-(4-(methylsulfonyl)phenyl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-3-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-1-methyl-3-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-1,3-diphenyl-1H-pyrazol-5-yl)urea;-   2-methoxyethyl 4-(5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-methyl-1H-pyrazol-3-yl)benzoate;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea;-   1-(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)-3-((3S,4R)-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5,5-dioxido-2-phenyl-4,6-dihydro-2H-thieno[3,4-c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-(methylsulfonyl)ethoxy)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea    hydrochloride;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea    hydrochloride;-   1-((3R,4S)-4-hydroxy-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3R,4S)-4-fluoro-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(trans-4-phenyl-1-(2-(trifluoromethoxy)ethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(trans-1-(2-(methylthio)ethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-1-((S)-2-methoxypropyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3,4-trans)-4-phenyl-1-(4,4,4-trifluorobutyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-1-(cyanomethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3,4-trans)-1-(cyanomethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-1-(cyanomethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   2-((3R,4S)-3-phenyl-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)acetamide;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxyethyl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((trans)-1-(3,3,4,4,4-pentafluorobutyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((trans)-1-ethyl-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-((trans)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-1H-pyrazol-5-yl)urea;-   1-((3R,4S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,3    S)-4-(3-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-((trans)-1-(1,3-difluoropropan-2-yl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   (trans)-tert-butyl    3-(3-methoxyphenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidine-1-carboxylate;-   1-((trans)-4-(3-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-(pyridin-2-yl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-((trans)-4-(4-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((trans)-4-(4-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((trans)-4-(2-chlorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)-3-((trans)-4-(pyridin-3-yl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-((trans)-4-(2-fluorophenyl)-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((trans)-4-(4-fluorophenyl)-1-(2,2-difluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(1H-pyrazol-3-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(3-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(3-(trifluoromethyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluoro-phenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-(3-methoxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-(2-methoxyethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(1H-pyrazol-4-yl)pyrrolidin-3-yl)-3-(3-(2-hydroxy-2-methylpropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(1-methyl-1H-pyrazol-5-yl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-1-(1-methyl-1H-pyrazol-5-yl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3R,4S)-4-(3,5-difluorophenyl)-1-(1-methyl-1H-pyrazol-5-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-phenylpyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyphenyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-fluorophenyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(4-fluorophenyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-methylphenyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyphenyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-chlorophenyl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-phenyl-1-(2-(trifluoromethoxy)phenyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-1-(2,6-difluorophenyl)-4-phenylpyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxypyridin-4-yl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxypyridin-3-yl)-4-phenylpyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-1-(2-ethoxypyridin-3-yl)-4-phenylpyrrolidin-3-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-1-(2-methoxypyridin-3-yl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3S,4R)-1-(2-methoxypyridin-3-yl)-4-phenylpyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H-pyrazol-5-yl)urea;-   1-(4-bromo-1′-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-1-(2-methoxypyridin-3-yl)-4-phenylpyrrolidin-3-yl)urea;-   1-(4-bromo-1,3-diphenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxypyridin-3-yl)-4-phenylpyrrolidin-3-yl)urea;-   1-((3    S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-(cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    11′H-3,4′-bipyrazol-5-yl)urea;-   1-((3S,4R)-1-((1,2,3-thiadiazol-4-yl)methyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-1H-imidazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-((1-methyl-1H-1,2,3-triazol-4-yl)methyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(1,3-dimethoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(1-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((trans)-4-(4-fluorophenyl)-1-(2-(methylamino)ethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((trans)-1-((1H-imidazol-2-yl)methyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   methyl    3-methoxy-2-((trans)-3-phenyl-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)propanoate;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(1-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(3-hydroxy-1-methoxy-3-methylbutan-2-yl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)ureido)pyrrolidin-1-yl)-3-methoxypropanoic    acid hydrochloride;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(4-chloro-1′-methyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(1-hydroxy-3-methoxypropan-2-yl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea;-   1-(3-(2-fluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-(3-(cyanomethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H,    1′H-3,4′-bipyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1′-methyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   (R,S)    1-((2α,3β,4α)-2-methyl-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   (R,S)-1-((3    (3,4α,5α)-5-methyl-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-hydroxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-((S)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(4-chloro-1′-methyl-1-phenyl-1H, 1′H-3,4′-bipyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-((R)-1,1,1-trifluoro-3-methoxypropan-2-yl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3 S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)    pyrrolidin-3-yl)-3-(3-methyl-4-(methylthio)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-methoxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-(1,1-difluoro-2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-(1,1-difluoro-2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-(1,1-difluoro-2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-(1,1-difluoro-2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxyethyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxy-2-methylpropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxypropyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   ethyl    5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylate;-   5-(3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide;-   1-(trans-4-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(trans-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(trans-4-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(trans-4-(3-chlorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(5-methyl-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-5-yl)urea;-   5-(3-(trans-4-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide;-   5-(3-(trans-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide;-   1-(trans-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(trans-4-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4,5′-trimethyl-1-phenyl-1H,    1′H-[3,3′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4,5′-trimethyl-1-phenyl-1H,    1′H-[3,3′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4,5′-trimethyl-1-phenyl-1H,    1′H-[3,3′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2′,4,5′-trimethyl-1-phenyl-1H,2′H-[3,3′-bipyrazol]-5-yl)urea;-   1-(4-cyclopropyl-1′-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-isopropyl-1′-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-ethyl-1′-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(4-fluorophenyl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(3-fluorophenyl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(2-fluorophenyl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(3-chlorophenyl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(1-(3-chloro-4-fluorophenyl)-1′,4-dimethyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(1-(3-chloro-2-fluorophenyl)-1′,4-dimethyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(4-fluorophenyl)-1′,4-dimethyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(3-fluorophenyl)-1′,4-dimethyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(2-fluorophenyl)-1′,4-dimethyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(3-chlorophenyl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(1-(3-chloro-4-fluorophenyl)-1′,4-dimethyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-((3S,4R)-4-(4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(1-(3-chloro-2-fluorophenyl)-1′,4-dimethyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3S,4R)-4-(2,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3-cyanophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(4-cyanophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(p-tolyl)pyrrolidin-3-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4,5-trifluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H-pyrazol-5-yl)urea;-   1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-trans-1-(2-methoxyethyl)-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-1-(2-methoxyethyl)-4-(1-methyl-1H-pyrazol-4-yl)pyrrolidin-3-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-((trans-1-(2-methoxyethyl)-4-(1,2,3-thiadiazol-4-yl)pyrrolidin-3-yl)urea;-   1-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)pyrroli-din-3-yl)urea;-   1-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(3-(trifluoromethyl)phenyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-((3R,4S)-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(3-(2-fluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-(2-fluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(trans-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   1-(trans-4-(5-chloropyridin-3-yl)-1-(2-methoxyethyl)    pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(trans-4-(5-chloropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(trans-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1,3-diphenyl-1H-pyrazol-5-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-(trans-4-(5-fluoropyridin-2-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3-fluoropyridin-4-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-1H-1,2,4-triazol-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(2-methoxyethyl)-4-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(3-cyano-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(2-hydroxyethyl)-4-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5-methyl-6-oxo-2-phenyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5-methyl-6-oxo-2-phenyl-2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((5-methyl-1,3,4-oxadiazol-2-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(4-chloro-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-fluoro-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(4-bromo-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxybutoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   ethyl 2-((5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)acetate;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxy-2-methylpropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-hydroxy-2-methylpropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((R)-3,3,3-trifluoro-2-hydroxypropoxy)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((S)-3,3,3-trifluoro-2-hydroxypropoxy)-1H-pyrazol-5-yl)urea;-   1-(4-chloro-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-((R)-2-hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-((R)-2-hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-((R)-2-hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-((R)-2-hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-((R)-2-hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-((R)-2-hydroxypropoxy)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxybutoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxybutoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxybutoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   ethyl    4-bromo-5-(3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-3-carboxylate;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(2-methoxyethyl)-4-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(2-methoxyethyl)-4-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methyl-2H-1,2,3-triazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-morpholinoethoxy)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   tert-butyl 4-(2-((5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)ethyl)piperazine-1-carboxylate;-   Trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenyl-2H-indazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenyl-2H-indazol-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-(pyrazin-2-yl)-1H-pyrazol-5-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-(pyridazin-4-yl)-2,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)urea;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl    dimethylcarbamate;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl    morpholine-4-carboxylate;-   1-(3-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea;-   1-(3-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea;-   1-(3-((S)-2-(tert-butyldimethylsilyloxy)propoxy)-4-methyl-1-phenyl-1-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea;-   1-(3-(2-hydroxy-2-methylpropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea;-   1-(3-((S)-2-(tert-butyldimethylsilyloxy)-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(methoxy-methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-(methoxy-methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(methoxy-methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-(methoxy-methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(methoxy-methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-(methoxy-methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(1,1-difluoro-2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(1,1-difluoro-2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(1,1-difluoro-2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-((S)-2-hydroxypropyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-((R)-2-hydroxypropyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-((R)-2-hydroxypropyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(2-hydroxy-2-methylpropyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(3-methyl-1,2,4-oxadiazol-5-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(2-cyanopropan-2-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1′-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1′-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1′-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-((3-4-(4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1′-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1′-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1′-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1′-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-phenyl-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1,3-diphenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1,3-diphenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1,3-diphenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1′-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-fluoro-1′-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-trans-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-trans-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1,3-diphenyl-1H-pyrazol-5-yl)-3-(trans-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1,3-diphenyl-1H-pyrazol-5-yl)-3-(trans-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-(trans-4-(5-fluoropyridin-2-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-1′-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-fluoro-1′-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(4-bromo-1′-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(5-fluoropyridin-3-yl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4,5-trifluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-(4-methoxybenzyl)-4-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea trifluoroacetate;-   2-(4-chloro-5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)ethyl    acetate;-   1-(4-chloro-3-(2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(trans-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(4-chloro-3-(cis-3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-((1r,3    S)-3-hydroxycyclobutyl)-1-phenyl-1H-pyrazol-5-yl)-3-(trans-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(trans-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(cis-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(trans-3-hydroxycyclobutyl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazole-3-carboxylic    acid;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N,4-dimethyl-1-phenyl-1H-pyrazole-3-carboxamide;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N,N,4-trimethyl-1-phenyl-1H-pyrazole-3-carboxamide;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N-ethyl-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N-isopropyl-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazole-3-carboxamide;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    1′H-3,4′-bipyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)urea;-   2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)acetate;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(3,3,3-trifluoro-2-hydroxypropyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-hydroxypropyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-1-(2-cyanoethyl)-4-(3,4-difluorophenyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   2-((3R,4S)-3-(3,4-difluorophenyl)-4-(3-(3-ethoxy-4-methyl-1-phenyl-1H-pyrazol-5-yl)ureido)pyrrolidin-1-yl)-N-methylacetamide;-   1-(1-cyclohexyl-3,4-dimethyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(3-hydroxy-2-(hydroxymethyl)propoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)urea;-   1-(3-(2,2-difluoroethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1-phenyl-3-(2,2,2-trifluoroethoxy)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1-phenyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-phenyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyridin-3-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyridin-4-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyridin-2-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(5-fluoropyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(5-fluoropyridin-3-yl)-4-methyl-1-(pyridin-3-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,3′-bipyrazol]-5-yl)urea;-   1-(1′,4-dimethyl-1-phenyl-1H, 1′H-[3,3′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    1′H-[3,3′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2′,4-dimethyl-1-phenyl-1H,2′H-[3,3′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-(5-fluoropyridin-3-yl)-1′,4-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-(5-methylpyridin-3-yl)-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(1-(5-chloropyridin-3-yl)-1′,4-dimethyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1′-(2,2,2-trifluoro-1-(2,2,2-trifluoroethoxy)ethyl)-1H,1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-1′-(2,2,2-trifluoroethyl)-1H,1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(1′-(cyclopropylmethyl)-4-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(1′-(cyclopropanecarbonyl)-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1′-(methylsulfonyl)-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-isopropyl-4-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyrimidin-5-yl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4,5′-trimethyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,3′,4-trimethyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(1′-cyclopropyl-4-methyl-1-phenyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylthiazol-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-methylpyrimidin-5-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-(2-aminopyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2,4-dimethylthiazol-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2,6-dimethylpyridin-4-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-(6-aminopyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(6-oxo-1-(2,2,2-trifluoroethyl)-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-isopropyl-4-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-bromo-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea;-   1-(3-(2-aminopyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3R,4S)-4-phenyl-1-(2,2,2-trifluoroethyl)pyrrolidin-3-yl)urea    bis(2,2,2-trifluoroacetate;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′-ethyl-4-methyl-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)urea;-   1-(1′-ethyl-4-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl    trifluoromethanesulfonate;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-(dimethylamino)pyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(2-methoxypyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-(2-(dimethylamino)pyrimidin-5-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(1′-ethyl-4-methyl-1-phenyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-cyclopropyl-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea    dihydrochloride;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(2-(piperazin-1-yl)ethoxy)-1H-pyrazol-5-yl)urea    trihydrochloride;-   1-(3-(benzyl oxy)-4-chloro-1-methyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   2-((5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)acetic    acid;-   2-((5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)-N-ethylacetamide;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-ethyl-3-(2-hydroxy-2-methylpropoxy)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-(2-aminoethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   N-(2-((5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-H-pyrazol-3-yl)oxy)ethyl)methanesulfonamide;-   N-(2-((5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)ethyl)acetamide;-   1-(3-(2-(4-acetylpiperazin-1-yl)ethoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   2-((5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-4-methyl-1-phenyl-1H-pyrazol-3-yl)oxy)acetamide;-   N-(5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethoxy-1-phenyl-1H-pyrazol-4-yl)-2,2,2-trifluoroacetamide;-   1-(4-amino-3-ethoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-ethoxy-4-(2-hydroxyethyl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-(4-methylpiperazin-1-yl)ethoxy)-1-phenyl-1H-pyrazol-5-yl)urea    trihydrochl oride;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(2-morpholino-2-oxoethoxy)-1-phenyl-1H-pyrazol-5-yl)urea;-   4-bromo-5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-3-carboxylic    acid;-   4-bromo-5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N-methyl-1-phenyl-1H-pyrazole-3-carboxamide;-   4-bromo-5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-N-methoxy-1-phenyl-1H-pyrazole-3-carboxamide;-   1-(4-chloro-1′-(2-methoxyethyl)-1-phenyl-1H,    1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-((R)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea;-   1-(3-((S)-2,3-dihydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea;-   1-(3-((S)-2-hydroxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((S)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-((R)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-((S)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea;-   1-(3-((R)-2-hydroxy-3-methoxypropoxy)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-1,1′-dimethyl-1H, 1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1,1′-dimethyl-1H,1′H-[3,4′-bipyrazol]-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   Tert-butyl 4-(4-chloro-5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)piperidine-1-carboxylate;-   1-(4-chloro-1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-3-(3,5-dimethylisoxazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   (R)-tert-butyl 2-(4-chloro-5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate;-   (S)-tert-butyl 2-(4-chloro-5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate;-   1-(4-bromo-1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   Tert-butyl 4-(4-bromo-5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)piperidine-1-carboxylate;-   1-(4-bromo-1-phenyl-3-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-bromo-3-(3,5-dimethylisoxazol-4-yl)-1-phenyl-1H-pyrazol-5-yl)-3-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   (R)-tert-butyl 2-(4-bromo-5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)pyrrolidine-1-carboxylate;-   tert-butyl 4-((4-bromo-5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazol-3-yl)methoxy)piperidine-1-carboxylate;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(piperidin-4-yl)-1H-pyrazol-5-yl)urea    dihydrochloride;-   1-(4-chloro-1-phenyl-3-(piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea    dihydrochloride;-   1-(4-bromo-1-phenyl-3-(piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea    dihydrochloride;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((R)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)urea    dihydrochloride;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((S)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)urea    dihydrochloride;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-chloro-1-phenyl-3-((R)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)urea    dihydrochloride;-   1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-((S)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)urea    dihydrochloride;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-chloro-1-phenyl-3-((S)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)urea    dihydrochloride;-   1-(4-bromo-1-phenyl-3-((R)-pyrrolidin-2-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea    dihydrochloride;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-((piperidin-4-yloxy)methyl)-1H-pyrazol-5-yl)urea    dihydrochloride;-   1-(4-chloro-1-phenyl-3-((piperidin-4-yloxy)methyl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea    dihydrochloride;-   1-(4-bromo-1-phenyl-3-((piperidin-4-yloxy)methyl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea    dihydrochloride;-   1-(4-bromo-3-(1-(methylsulfonyl)piperidin-4-yl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-(1-acetylpiperidin-4-yl)-4-bromo-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-chloro-1-phenyl-3-(1-(trifluoromethylsulfonyl)piperidin-4-yl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea    hydrochloride;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((R)-1-(methylsulfonyl)pyrrolidin-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-(3-((R)-1-acetylpyrrolidin-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((R)-1-methylpyrrolidin-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea    dihydrochloride;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-((S)-1-methylpyrrolidin-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea    dihydrochloride;-   1-(4-bromo-3-((1-(methylsulfonyl)piperidin-4-yloxy)methyl)-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(3-((1-acetylpiperidin-4-yloxy)methyl)-4-bromo-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-(4-isopropyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-4-methyl-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-1-phenyl-3-(pyrazin-2-yloxy)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methoxy-1-phenyl-4-(trifluoromethyl)-1H-pyrazol-5-yl)urea;-   1-((trans)-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea;-   1-((trans)-4-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)    pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea;-   1-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea;-   1-((3    S,4R)-1-(2-methoxyethyl)-4-(3,4,5-trifluorophenyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea;-   1-((3S,4R)-4-(3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea;-   1-((trans)-4-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea;-   1-(4-cyano-3-methoxy-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-((3 S,4R)-4-(3-chl    oro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)urea;-   1-(4-cyano-1-phenyl-3-(trifluoromethyl)-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   1-(4-cyano-5-oxo-2-phenyl-2,5-dihydro-1H-pyrazol-3-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)urea;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-methoxy-1-phenyl-1H-pyrazole-4-carboxamide;-   5-(3-((3    S,4R)-4-(3,4-difluoro-phenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-ethyl-1-phenyl-1H-pyrazole-4-carboxamide;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-3-(trifluoromethyl)-1H-pyrazole-4-carboxamide;-   5-(3-((trans)-4-(3-chloro-4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide;-   5-(3-((trans)-4-(4-chloro-3-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide;-   5-(3-((trans)-4-(3-chloro-5-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide;-   5-(3-((3    S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-3-methyl-1-phenyl-1H-pyrazole-4-carboxamide;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carboxamide;-   5-(3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)ureido)-1-phenyl-1H-pyrazole-4-carboxamide;-   1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)guanidine    dihydrochloride;-   1-(4-bromo-3-methyl-1-phenyl-1H-pyrazol-5-yl)-3-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)thiourea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(4-methyl-3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-1-phenyl-1H-pyrazol-5-yl)thiourea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,    1′H-3,4′-bipyrazol-5-yl)thiourea;-   1-((3    S,4R)-4-(4-fluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1′,4-dimethyl-1-phenyl-1H,1′H-3,4′-bipyrazol-5-yl)thiourea;-   Trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)urea;-   Trans-1-(2-methoxyethyl)-4-phenylpyrrolidin-3-yl)-3-(pyrazolo[1,5-a]pyridin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(pyrazolo[1,5-a]pyridin-3-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5-methyl-3-phenyl-1-(pyrazin-2-yl)-1H-pyrazol-4-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl)urea;-   1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1,5-dimethyl-3-phenyl-1H-pyrazol-4-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-isopropyl-5-methyl-3-phenyl-1H-pyrazol-4-yl)urea;-   1-((3S,4R)-4-(3,5-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-isopropyl-5-methyl-3-phenyl-1H-pyrazol-4-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(5-methyl-3-phenyl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-4-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-ethyl-5-methyl-3-phenyl-1H-pyrazol-4-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-ethyl-3-methyl-5-phenyl-1H-pyrazol-4-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-5-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)urea;-   1-((3S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-methyl-3-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)urea;-   1-((3    S,4R)-4-(3,4-difluorophenyl)-1-(2-methoxyethyl)pyrrolidin-3-yl)-3-(1-phenyl-3-(trifluoromethyl)-1H-pyrazol-4-yl)urea;-   or a pharmaceutically acceptable salt thereof.-   In some embodiments, a Trk inhibitor is selected from the group    consisting of:-   5-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-phenylethyl)pyrimidine-2,4-diamine;-   5-Bromo-N-(3-ethyl-1H-pyrazol-5-yl)-N²-(1-phenylethyl)    pyrimidine-2,4-diamine;-   N⁴-(3-tert-Butyl-1H-pyrazol-5-yl)-5-chloro-N²-(1-phenylethyl)pyrimidine-2,4-diamine;-   N⁴-(3-Cyclopropyl-1H-pyrazol-5-yl)-N²-(1-phenylethyl)-5-(trifluoromethyl)pyrimidine-2,4-diamine:-   5-Bromo-N⁴-(3-cyclopropyl-1H-pyrazol-5-yl)-N²-[(1    S)-1-(4-fluorophenyl)ethyl]pyrimidine-2,4-diamine:-   5-Bromo-N⁴-(3-cyclopropyl-1    I-pyrazol-5-yl)-N²-[(1S)-1-phenylpropyl]pyrimidine-2,4-diamine;-   5-Bromo-N⁴-(3-cyclopropyl-1H-pyrazol-5-yl)-N²-[(1    S)-1-(4-nitrophenyl)ethyl]pyrimidine-2,4-diamine;-   (2R)-2-({5-Bromo-4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrimidin-2yl}amino)-2-phenylethanol;-   5-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N²-(1-phenylethyl)pyrimidine-2,4-diamine;-   5-Chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-N-(1-phenylpropyl)pyrimidine-2,4-diamine,

or a pharmaceutically acceptable salt thereof.

In some embodiments, a Trk inhibitor is one or more compounds of Table5, or a pharmaceutically acceptable salt thereof.

TABLE 5 Exemplary Trk inhibitors Compound No. Compound StructureCompound Name 1

(R)-N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3- hydroxyazetidine-1-carboxamide 2

(R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1,1- dimethylurea 3

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea 4

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3- methylurea 5

(R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3- hydroxyazetidine-1-carboxamide 6

(R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1-(2- hydroxyethyl)-1-methylurea 7

(R)-N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide 8

(R)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1,1- dimethylurea 9

(R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide 10

(R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy-3-methylazetidine-1- carboxamide 11

(R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3- hydroxyazetidine-1-carboxamide 12

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13

(R)-N-cyclopropyl-5-(2-(5-fluoro- pyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 14

(R)-5-(2-(5-fluoro-2-methoxypyridin- 3-yl)pyrrolidin-1-yl)-N-methoxy-pyrazolo[1,5-a]pyrimidine-3- carboxamide 15

(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo [1,5-a]pyrimidine-3-carboxamide 16

(6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]-hexacosa-1(25),7,9,11,19(26),20,23- heptaen-18-one 17

(6R,15R)-9-fluoro-15-hydroxy-13-oxa- 2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0^(2,6).0^(7,12).0^(22,26)]-hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one 18

(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0^(2,6).0^(7,12).0^(23,27)]-heptacosa-1(26),7,9,11,20(27),21,24- heptaen-19-one 19

(6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23- heptaen-18-one 20

(6R)-12-oxa-2,16,20,21,24,26-hexaazapentacyclo[16.5.2.^(17,11).0^(2,6).0^(21,25)]-hexacosa-1(24),7(26),8,10,18(25),19,22- heptaen-17-one 21

1-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22- heptaen-16-yl]ethan-1-one 22

(6R)-9-fluoro-13,16-dioxa-2,11,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]-pentacosa-1(24),7,9,11,18(25),19,22- heptaen-17-one 23

(6R)-9,15,15-trifluoro-13-oxa-2,11,17,21, 22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one 24

(6R,13S)-9-fluoro-13-methyl-2,11,15, 19,20,23-hexaazapentacyclo[15.5.2.^(17,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),18,21-hexaene- 16,25-dione 25

(6R)-9-fluoro-15,15-dimethyl-13-oxa- 2,11,17,21,22,25-hexaazapentacyclo[17,5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen- 18-one 26

(15S)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17,21,22.25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen- 18-one 27

(6R,15S)-9-fluoro-15-methyl-2,11,16, 20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen- 17-one 28

(6R,15R)-9-fluoro-15-methyl-2,11,16,20, 21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17- one

Additional examples of Trk inhibitors are described in U.S. PatentApplication Ser. No. 62/080,374, International Application PublicationNos. WO 11/006074, WO 11/146336, WO 10/033941, and WO 10/048314, andU.S. Pat. Nos. 8,933,084, 8,791,123, 8,637,516, 8,513,263, 8,450,322,7,615,383, 7,384,632, 6,153,189, 6,027,927, 6,025,166, 5,910,574,5,877,016, and 5,844,092, each of which is herein incorporated byreference in its entirety. Additional Trk inhibitors are known in theart.

In some embodiments, a first Trk inhibitor is selected from the groupconsisting of: entrectinib(N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide);(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate; cabozantinib((N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclpropane-1,1-dicarboxamide));dovatinib(4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-onemono 2-hydroxypropanoate hydrate); belizatinib(4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)benzamide);sitravatinib(N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);PLX7486; altiratinib(N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);and AZD7451((S)—N-(1-(5-fluoropyrimidin-2-yl)ethyl)-3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine)).For example, a first Trk inhibitor can be entrectinib orS)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (or a polymorph thereof).

In some embodiments, a second Trk inhibitor is a compound of Table 5, ora pharmaceutically acceptable salt thereof.

In some embodiments, a second Trk inhibitor does not include a compoundselected from the group consisting of: entrectinib(N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide);(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate; cabozantinib((N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide));dovatinib(4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-onemono 2-hydroxypropanoate hydrate); belizatinib(4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)benzamide);sitravatinib(N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);PLX7486; altiratinib(N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);and AZD7451((S)—N-(1-(5-fluoropyrimidin-2-yl)ethyl)-3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine)).

Further provided herein are pharmaceutical compositions containing oneor more Trk inhibitors as provided herein with a pharmaceuticallyacceptable carrier. Pharmaceutical compositions containing one or moreTrk inhibitors as the active ingredient can be prepared by mixing theTrk inhibitor with a pharmaceutical carrier according to conventionalpharmaceutical techniques. The carrier may take a wide variety of formsdepending upon the desired route of administration (e.g., oral,parenteral). Thus for liquid oral preparations such as suspensions,elixirs and solutions, suitable carriers and additives include water,glycols, oils, alcohols, flavoring agents, preservatives, stabilizers,coloring agents and the like; for solid oral preparations, such aspowders, capsules and tablets, suitable carriers and additives includestarches, sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Solid oral preparations may also becoated with substances such as sugars or be enteric-coated so as tomodulate major site of absorption. For parenteral administration, thecarrier will usually consist of sterile water and other ingredients maybe added to increase solubility or preservation. Injectable suspensionsor solutions may also be prepared.

In some embodiments, a Trk inhibitor as provided herein can beadministered as a tablet or capsule.

In some embodiments, a Trk inhibitor provided herein can be administeredas a liquid formulation. For example, provided herein is a liquidformulation including:

(a)(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidehaving the Formula I:

a pharmaceutically acceptable salt thereof, or a combination thereof;

(b) a solubilizing agent (e.g., a cyclodextrin such as ahydroxypropyl-β-cyclodextrin) present in an amount of about 5 wt. % toabout 35 wt. %; and

(c) a buffer (e.g., a citrate buffer such as sodium citrate) present inan amount of about 0.1 wt. % to about 5 wt. %;

(d) a sweetener (e.g., a sweetener comprising sucrose or an intensesweetener) present in an amount of about 30 wt. % to about 70 wt. %;

(e) a bitterness masking agent present in an amount of about 0.2 wt. %to about 0.5 wt. %; and

(f) a flavoring agent present in an amount of about 0.01 wt. % to about2 wt. %. In some embodiments, the formulation has a pH of about 3 toabout 4. In some embodiments, the compound of Formula I has aconcentration of about 20 mg/mL to about 30 mg/mL in the liquidformulation. Further examples of a liquid formulation can be found inU.S. Provisional Ser. Nos. 62/380,773 and 62/329,561, both of which areincorporated by reference in their entireties herein.

In some embodiments, the liquid formulation is prepared from apharmaceutically acceptable salt of the compound of Formula I. Forexample, the pharmaceutically acceptable salt is a hydrogen sulfatesalt. In some embodiments, the liquid formulation is prepared from acrystalline form of the compound of Formula I. For example, thecrystalline form of the compound of Formula I can have the Formula I-HS:

In the methods provided herein, a Trk inhibitor can be orally,subcutaneously, intraperitoneally, intravenously, or intramuscularlyadministered. In some examples, a Trk inhibitor can be administered inone or more doses including between about 1 mg and about 250 mg, betweenabout 1 mg and about 200 mg, between about 1 mg and about 180 mg,between about 1 mg and about 160 mg, between about 1 mg and about 140mg, between about 1 mg and about 120 mg, between about 1 mg and about100 mg, between about 1 mg and about 80 mg, between about 1 mg and about60 mg, between about 1 mg and about 40 mg, between about 1 mg and about40 mg, between about 10 mg and about 200 mg, between about 10 mg andabout 180 mg, between about 10 mg and about 160 mg, between about 10 mgand about 140 mg, between about 10 mg and about 120 mg, between about 10mg and about 100 mg, between about 10 mg and about 80 mg, between about10 mg and about 60 mg, between about 10 mg and about 40 mg, betweenabout 10 mg and about 20 mg, between about 20 mg and about 200 mg,between about 20 mg and about 180 mg, between about 20 mg and about 160mg, between about 20 mg and about 140 mg, between about 20 mg and about120 mg, between about 20 mg and about 100 mg, between about 20 mg andabout 80 mg, between about 20 mg and about 60 mg, between about 20 mgand about 40 mg, between about 40 mg and about 200 mg, between about 40mg and about 180 mg, between about 40 mg and about 160 mg, between about40 mg and about 140 mg, between about 40 mg and about 120 mg, betweenabout 40 mg and about 100 mg, between about 40 mg and about 80 mg,between about 40 mg and about 60 mg, between about 60 mg and about 200mg, between about 60 mg and about 180 mg, between about 60 mg and about140 mg, between about 60 mg and about 120 mg, between about 60 mg andabout 100 mg, between about 60 mg and about 80 mg, between about 80 mgand about 200 mg, between about 80 mg and about 180 mg, between about 80mg and about 160 mg, between about 80 mg and about 140 mg, between about80 mg and about 120 mg, between about 80 mg and about 100 mg, betweenabout 90 mg and about 110 mg, between about 95 mg and about 105 mg,between about 100 mg and about 200 mg, between about 100 mg and about180 mg, between about 100 mg and about 160 mg, between about 100 mg andabout 140 mg, between about 100 mg and about 120 mg, between about 120mg and about 200 mg, between about 120 mg and about 180 mg, betweenabout 120 mg and about 160 mg, between about 120 mg and about 140 mg,between about 140 mg and about 200 mg, between about 140 mg and about180 mg, between about 140 mg and about 160 mg, between about 160 mg andabout 200 mg, between about 160 mg and about 200 mg, between about 160mg and about 180 mg, or between about 180 mg and about 200 mg of the Trkinhibitor. The appropriate dose of a Trk inhibitor to be administered toa subject can be determined by a medical professional, e.g., based uponone or more of the subject's mass, the subject's condition, subject'sgender, and the other diseases that the subject may have.

Multiple doses of the Trk inhibitor (e.g., any of the doses describedherein) can be administered once every six months, once every fivemonths, once every four months, once every three months, once every twomonths, once every six weeks, once a month, once every three weeks, onceevery two weeks, once a week, twice a week, three times a week, fourtimes a week, three times a week, every other day, once a day, twice aday, or three times a day as part of a treatment. The Trk inhibitor canbe self-administered (e.g., by the subject having a cancer) or can beadministered by a health care professional (e.g., a physician, a nurse,a physician's assistance, or a pharmacist) as part of a treatment asdescribed herein.

Treatments that do not Include a Trk Inhibitor as a Monotherapy andAdditional Anticancer Agents and Therapies

In any of the methods described herein, a treatment that does notinclude a Trk inhibitor (e.g., a first Trk inhibitor as describedherein) (e.g., entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) as a monotherapy can be, e.g., a treatment that includesanother anticancer agent or anticancer therapy. In some embodiments, atreatment that does not include a Trk inhibitor as a monotherapy can be,for example, a treatment that includes one or more of: surgery,radiation therapy, chemotherapy, immunotherapy, hormone therapy, smallmolecule drugs targeting other kinases in a Trk-signaling pathway,recombinant antibodies, and stem cell transplant. In some embodiments,an additional anticancer agent is selected from the group consisting of:chemotherapy, immunotherapy, hormone therapy, small molecule drugstargeting other kinases in a Trk-signaling pathway, and recombinantantibodies. In some embodiments, an anticancer therapy is selected fromthe group consisting of: surgery, radiation therapy, and stem celltransplant.

In some embodiments, a treatment that does not include a Trk inhibitor(e.g., a first Trk inhibitor) as a monotherapy can be, e.g., acombination treatment that includes (i) one or more of surgery,radiation therapy, chemotherapy, immunotherapy, hormone therapy, smallmolecule drugs targeting other kinases in a Trk-signaling pathway,recombinant antibodies, and stem cell transplant, and (ii) one or moreTrk inhibitors (e.g., any of the Trk inhibitors described herein). Insome embodiments, a treatment that does not include a Trk inhibitor as amonotherapy can be, e.g., a treatment that includes two or more Trkinhibitors (e.g., any of the Trk inhibitors described herein).

In some embodiments, a treatment that does not include a first Trkinhibitor as a monotherapy can be, e.g., a treatment that includes asecond Trk inhibitor as a monotherapy. In some embodiments, a treatmentthat does not include a first Trk inhibitor as a monotherapy can be,e.g., a treatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof.

Non-limiting examples of surgery include, e.g., open surgery orminimally invasive surgery. Surgery can include, e.g., removing anentire tumor, debulking of a tumor, or removing a tumor that is causingpain or pressure in the subject. Methods for performing open surgery andminimally invasive surgery on a subject having a cancer are known in theart.

Non-limiting examples of radiation therapy include external radiationbeam therapy (e.g., external beam therapy using kilovoltage X-rays ormegavoltage X-rays) or internal radiation therapy. Internal radiationtherapy (also called brachytherapy) can include the use of, e.g.,low-dose internal radiation therapy or high-dose internal radiationtherapy. Low-dose internal radiation therapy includes, e.g., insertingsmall radioactive pellets (also called seeds) into or proximal to acancer tissue in the subject. High-dose internal radiation therapyincludes, e.g., inserting a thin tube (e.g., a catheter) or an implantinto or proximal to a cancer tissue in the subject, and delivering ahigh dose of radiation to the thin tube or implant using a radiationmachine. Methods for performing radiation therapy on a subject having acancer are known in the art.

In some embodiments provided herein, an additional anticancer agent isadministered. Non-limiting examples of such additional anticancer agentsare as follows.

Non-liming examples of chemotherapy include, e.g., an alkylating agent,an antimetabolite, an anti-microtubule agent, a topoisomerase inhibitor,and a cytotoxic antibiotic. Examples of alkylating agents include, e.g.,nitrogen mustards (e.g., cyclophosphamide, mechlorethamine or mustine,uramustine or uracil mustard, melphalan, chlorambucil, ifosfamide, andbendamustine), nitrosoureas (e.g., carmustine, lomustine, andstreptozocin), and alkyl suflonates (e.g., busulfan). Additionalexamples of alkylating agents include, e.g., cisplatin, carboplatin,nedaplatin, oxaliplatin, satraplatin, triplatin tetranitrate,procarbazine, altretamine, dacarbazine, mitozolomide, and temozolomide.Non-limiting examples of anti-metabolites include fluorouracil,cladribine, capecitabine, mercaptopurine, pemetrexed, fludarabine,gemcitabine, hydroxyurea, methotrexate, nelarabine, clofarabine,cytarabine, decitabine, pralatrexate, floxuridine, and thioguanine.Non-limiting examples of anti-microtubule agents include colchicine,dolastatin 15, nocodazole, paclitaxel, podophyllotoxin, rhizoxin,vinblastine, vincristine, vindesine, and vinorelbine. Non-limitingexamples of topoisomerase inhibitors include camptosar, hycamtin,irinotecan, topotecan, voreloxin, camptothecin, SN-38, gimatecan,belotecan, lurtotecan, exatecan, diflometecan, S 39625, NSC 314622, NSC706744, NSC 725776, NSC 724998, topovale (ARC-111), endotecarin(ED-709), BMS-250749, and indenoisoquinoline. Non-limiting examples ofcytotoxic antibiotics include bleomycin, dactinomycin, daunorubicin,plicamycin, mitomycin, mitoxantrone, daunorubicin, doxorubicin,epirubicin, idarubicin, and mitoxantrone. Additional examples ofchemotherapy are known in the art.

Non-limiting examples of immunotherapy include adoptive cell transfer, acytokine, a cancer vaccine, bispecific T cell engagers (e.g., Huehls etal., Immunol. Cell Biol. 93:290-296, 2015), and BacillusCalmette-Guérom. Non-limiting examples of adoptive cell transfer includetumor infiltrating lymphocytes (Demaria et al., Clin. Cancer Res.7:3025-3030, 2001), sensitized B cells (Li et al., J. Immunol.183:3195-3203, 2009), sensitized T cells (Wang et al., Breast CancerRes. Treatment 134:61-70, 2012), antigen-loaded dendritic cells(Ponsaerts et al., Clin. Exp. Immunol. 134:378-384, 2003), chimericantigen receptor-T cells (CAR-T cells) (Hinrichs et al., Immunol. Rev.257:56-71, 2014), artificial antigen presenting cells (aAPCs) (e.g.,Turtle et al., Cancer J. 16:374-381, 2010), immunomodulated NK cells(e.g., Flannery et al., Eur. J. Cancer Clin. Oncol. 20:791-798, 1984),and T cells genetically engineered with T cell receptors (e.g., Essandet al., J. Intern Med. 273:166-181, 2013). Additional examples ofimmunotherapy are known in the art.

Non-limiting examples of hormone therapy include drugs that blockestrogen, drugs that lower estrogen levels, progesterone-like drugs, andanti-androgen drugs. Examples of drugs that block estrogen include,e.g., vorozole, testolactone, formestane, tamoxifen, clomifene,arzooxifene, clomiphene, anastrozole, lentrozole, exemestane,raloxifene, toremifene, and fulvestrant. Examples of anti-progestroneagent of mifepristone and aglepristone. Examples of drugs that areanti-androgen drugs include, e.g., bicalutamide, flutamide, nilutamide,and enzalutamide. Additional examples of hormone therapy are known inthe art.

Non-limiting examples of small molecule drugs targeting other kinases ina Trk-signaling pathway including inhibitors of PI3K, Akt, Ras, Raf,MEK, and ERK. Examples of a PI3K include A-769662, acalisib (GS-9820 orCAL-120), afuresertib (GSK-2110183), AMG-319, ARQ-092, AS-252424,AS-604850, AS-605240, AZD6482, BAY 80-6940, BEZ235 (NVP-BEZ235),BGT-226, buparlisib (BKM120), BYL719, CAL-101, CAY10505, CC-115, CC-223,CH5132799, copanlisib (BAY 80-6946), CUDC-907, CZC24832, D-106669,D-116883, D-87503, deguelin, DS-3078a, duvelisib (IPI-145), everolimus(RAD001), GDC-0032, GDC-0349 (RG7603), GDC-0980 (RG7422), GSK1059615,GSK2126458, GSK-2141795, HS-173, IC-87114, idelalisib (CAL-101 orGS-1101), INCB040093, INK1117, LY2780301, LY294002 (SF1101), MK-2206,MLN0128, NU7441, OSI-027, panulisib, PF-04691502, PF376304, phenforminhydrochloride, PI-103, pictilisib (GDC-0941 or RG7321), PIK-124,PIK-294, PIK-39, PIK-90, PIK-93, PIK-402, PKI-587, PP121, PWT33597,PX-866, quercetin (sophoretin), ridaforolimus, rigosertib (ON 01910.Na),RP-6539, SAR245408 (XL147), SAR260301, SF1126, SF1326, sirolimus,staurosporine, TASP0415914, temsirolimus, TG100-115, TGR-1202, TGX221,theophylline, triciribine, VS-5584, wortmannin, XL-765 (SAR245409), andZSTK474.

Non-limiting examples of Akt inhibitors include A-443654, A-674563,afuresertib (GSK-2110183), API-1, ARQ-094, AT7867, AZ7328, AZD-5363,CCT128930, DC120, deguelin, GDC-0068, GSK-2141795, GSK-690693, ISC-4,KP372-1, LY2780301, LY294002, Y294005, MK-2206, oleandrin (PBI-05204),palomid 529, perifosine, PF-AKT400, PHT-427, PX-316, SC66, semaxanib,SH-5, SR13668, temsirolimus, trametinib, and triciribine.

Non-limiting examples of Ras inhibitors include Kobe2602, manumycin A,L-744,832 dihydrochloride, farnesyl thiosalicylic acid, FTI-276trifluoroacetate salt, SCH 51344, tipifarnib, and K-ras(G12C) inhibitor12, and K-ras(G12C) inhibitor 6. Non-limiting examples of Raf inhibitorsinclude sorafenib (Nexavar or BAY 43-9006), GDC0879, RAF265, dabrafenib(GSK2118436), vemurafenib (PLX-4032), SB590885, PLX-4720, encorafenib(LGX818), LY3009120, AZ 628, CEP-32496, TAK-632, ZM 336372, NVP-BHG712,and GW5074.

Non-limiting examples of MEK inhibitors include CI-1040, trametinib(GSK1120212), selumetinib (AZD6244), binimetinib (MEK162, ARRY-162, orARRY-438162), PD-325901, cobimetinib (XL518), CI-1040, PD035901, U0126,PD184352 (CI-1040), PD98059, BIX 02189, pimasertib (AS-703026), BIX02188, TAK-733, AZD8330, PD318088, honokiol, SL-327, refametinib(RDEAI19 or Bay 86-9766), GDC-0623, and BI-847325.

Non-limiting examples of ERK inhibitors include SCH772984, XMD8-92, FR180204, GDC-0994, ERK5-IN-1, ulixertinib (BVD-523 or VRT752271),FR180204, BIX 02189, pluripotin, TCS ERK lie, TMCB, XMD 8-92, U0126,trametinib, and selumetinib.

Non-limiting examples of recombinant antibodies include monoclonalantibodies, bispecific antibodies (e.g., BiTE® antibodies), Fab, Fab2,Fab3, scFv, Bis-scFv, minibody, triabody, diabody, tetrabody, VhHdomain, V-NAR domain, IgNAR, and camel Ig. Additional examples of arecombinant antibody (e.g., a recombinant human antibody) are IgG (e.g.,IgG1, IgG2, IgG3, or IgG4), IgM, IgE, IgD, and IgA. Non-limitingexamples of recombinant antibodies include human antibodies, humanizedantibodies, or chimeric antibodies. Non-limiting examples of recombinantantibodies include antibodies that specifically bind to NGF.

Non-limiting examples of recombinant antibodies that bind specificallyto NGF include tanezumab, futuximab, MNAC13, fasinumab (REGN475), mAbNGF30 (e.g., Saragovi et al., J. Biol. Chem. 273:34933-34940, 1998),ME20.4, and ME82.11. Additional antibodies that bind specifically to NGFare described, e.g., in U.S. Pat. Nos. 8,106,167; 8,148,107; and8,911,734; U.S. Patent Application Publication Nos. 2009/0041717,2011/0268725, and 2014/0227287; International Patent ApplicationPublication Nos. WO 06/131051 and WO 12/024650; and European Patent No.18646451.

Additional examples of recombinant antibodies include, e.g., 3F8, 8H9,abagovomab, abituzumab, adecatumumab, afutuzumab, alacizumab pegol,alemtuzumab, altumomab pentetate, amatuximab, anatumomab mefanetox,anetumab ravtansine, apolizumab, arcitumomab, ascrinvacumab,atezolizumab, bavituximab, bectumomab, belimumab, besilesomab,bevacizumab, bivatuzumab mertansine, blinatumomab, brentuximab,brontictuzumab, cantuzumab mertansine, cantuzumab ravansine, capromabpendetide, carlumab, catumaxomab, cBR96-doxorubicin immunoconjugate,CC49, cetuximab, Ch. 14.18, citatuzumab bogatox, cixutumumab,clivatuzumab tetraxetan, codrituzumab, coltuximab ravtansine,conatumumab, dacetuzumab, dalotuzumab, daratumumab, demcizumab,denintuzumab mafodotin, denosumab, derlotuximab biotin, detumomab,dinutuximab, drozitumab, durvalumab, dusigitumab, ecromeximab,edrecolomab, elgemtumab, elotuzumab, emactuzumab, emibetuzumab,enavatuzumab, enfortunmab vedotin, enoblituzumab, ensituximab,epratuzumab, ertumaxomab, etaracizumab, farletuzumab, FBTA05,ficlatuzumab, figitumumab, flanvotumab, galiximab, ganitumab, gemtuzumabozogamicin, girentuximab, glembatumumab vedotin, ibritumomab, icrucumab,igovomab, IMAB362, imalumab, imgatuzumab, indatuzimab ravtansine,indusatumab vedotin, intetumumab, inotuzumab ozogamicin, ipilimumab,iratumumab, isatuzimab, labetuzumab, lambrolizumab, lexatumumab,lifastuzumab vedotin, lilotomab satetraxetan, lintuzumab, lorvotuzumabmertansine, lucatumumab, lumiliximab, lumretuzumab, mapatumumab,margetuximab, matuzumab, milatuzumab, mirvetuximab soravtansine,mitumomab, mogamulizumab, moxetumomab pasudotox, nacolomab tafenatox,naptumomab estafenatox, narnatumab, necitumumab, nesvacumab,nimotuzumab, nivolumab, nofetumomab merpentan, obinutuzumab,ocaratuzumab, ofatumumab, olaratumab, onartuzumab, ontuxizumab,oportuzumab monatox, oregovomab, otlertuzumab, panitumumab, pankomab,parsatuzumab, pasotuxizumab, patritumab, pembrolizumab, pemtumomab,pertuzumab, pidilizumab, pinatuzumab vedotin, pintumomab, polatuzumabvedotin, pritumumab, racotumomab, radretumab, ramucirumab, rilotumumab,rituximab, robatumumab, sacituzumab govitecan, samalizumab, satumomabpendetide, seribantumab, sibrotuzumab, SGN-CD19A, SGN-CD33A, siltuximab,sofituzumab vedotin, tabalumab, tacatuzumab tetraxetan, taplitumomabpaptox, tarextumab, tenatumomab, teprotumumab, TGN1412, ticilimumab(tremelimumab), tigatuzumab, TNX-650, tositumomab, tovetumab,trastuzumab, TRBS07, tremelimumab, tucotuzumab celmoleukin, ublituximab,ulocuplumab, urelumab, vandortuzumab vedotin, vantictumab, vanucizumab,veltuzumab, volociximab, vorsetuzumab mafodotin, votumumab, zalutumamab,zanolimumab, and zatuximab.

Non-limiting examples of stem cell transplant include autologous stemcell transplant, allogeneic stem cell transplant, and syngeneic stemcell transplant. Methods for performing autologous stem cell transplantare described in, e.g., Perales et al., Biol. Blood Marrow Transplant.,e-published ahead of print, 2015; and Isdori et al., World J. Stem Cells7:1039-1046, 2015. Methods for performing allogeneic stem celltransplant is described in, e.g., Imamura et al., Exp. Hematol. Oncol.4:20, 2015; Hobbs et al., J. Clin. Med. 19:488-503, 2015; and Bensingeret al., Stem Cells 14:90-105, 1996. Methods for performing syngeneicstem cell transplant are described in, e.g., Engman et al., Clin. Adv.Heamtol. Oncol. 7:321-323, 2009; and Richard et al., Br. J. Haematol.117:245-246, 2002. Additional methods for isolating stem cells andadministering stem cells to a subject are known in the art.

In some examples, the subject is hospitalized or receives a treatmentnot including a Trk inhibitor as a monotherapy on in inpatient basis. Inother examples, the subject is treated or receives a treatment notincluding a Trk inhibitor as a monotherapy on an outpatient basis.

In some examples, the subject is hospitalized or receives a treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, and an additional anticancer agent oranticancer therapy including one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, on an inpatient basis. Inother examples, the subject is treated or receives a treatment includingone or more compounds of Table 5, or a pharmaceutically acceptable saltthereof, and an additional anticancer agent or a treatment including oneor more compounds of Table 5, or a pharmaceutically acceptable saltthereof, on an outpatient basis.

Methods of Treating a Subject Having a Cancer

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include identifying a subjecthaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more of the amino acid positions shown in Tables 1, 2, or 3, andadministering to the identified subject a treatment that does notinclude a Trk inhibitor (e.g., a first Trk inhibitor such as entrectinibor(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) as a monotherapy (e.g., any of treatments that do not include aTrk inhibitor as a monotherapy described herein).

Also provided herein are methods of treating a subject having a cancer(e.g., any of the cancers described herein) and identified as having acancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3) that includeadministering to the identified subject a treatment that does notinclude a Trk inhibitor (e.g., a first Trk inhibitor such as entrectinibor(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) as a monotherapy (e.g., any of treatments that do not include aTrk inhibitor as a monotherapy described herein).

Also provided herein are methods of treating a subject that includeadministering a therapeutically effective amount of a treatment thatdoes not include a Trk inhibitor (e.g., a first Trk inhibitor) as amonotherapy, to a subject having a clinical record that indicates thatthe subject has a cancer cell that has at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancer(e.g., any of the cancers described herein or known in the art) thatinclude: identifying a subject having a cancer cell that has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3); and administering to the identified subject atreatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof.

Also provided herein are methods of treating a subject having a cancer(e.g., any of the cancers described herein or known in the art) thatinclude: identifying a subject having a cancer cell that has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3); and administering to the identified subject atreatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, and another anticancer agent(e.g., any one or more of the anticancer agents described herein) oranticancer therapy (e.g., any one or more of the anticancer therapiesprovided herein.

Also provided herein are methods of treating a subject identified ashaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3), that includeadministering to the subject a treatment that includes one or morecompounds of Table 5, or a pharmaceutically acceptable salt thereof.

Also provided herein are methods of treating a subject identified ashaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3), that includeadministering to the subject a treatment that includes one or morecompounds of Table 5, or a pharmaceutically acceptable salt thereof, andanother anticancer agent (e.g., any one or more of the anotheranticancer agents described herein) or anticancer therapies (e.g., anyone or more of the anticancer therapies described herein).

Also provided herein are methods of treating a subject that includeadministering a therapeutically effective amount of a treatment thatincludes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, to a subject having a clinical record thatindicates that the subject has a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3).

Also provided herein are methods of treating a subject that includeadministering a therapeutically effective amount of a treatment thatincludes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, and another anticancer agent (e.g., any one ormore of the anticancer agents described herein) or anticancer therapies(e.g., any one or more of the anticancer therapies described herein), toa subject having a clinical record that indicates that the subject has acancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancerthat include (a) administering one or more doses Trk inhibitor (e.g., afirst Trk inhibitor, such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) to the subject for a period of time; (b) after (a), determiningwhether a cancer cell in a sample obtained from the subject has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3), and (c) administering a different Trk inhibitor or atreatment that does not include the Trk inhibitor of step (a) as amonotherapy to a subject having a cancer cell that has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more of the amino acid positions shown in Tables 1,2, or 3); or (d) administering additional doses of the Trk inhibitor ofstep (a) to a subject having a cancer cell that does not have at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancerthat include: (a) determining whether a cancer cell in a sample obtainedfrom a subject having a cancer and previously administered one or moredoses of a Trk inhibitor (e.g., a first Trk inhibitor such asentrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate), has at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); (b) administering a different Trkinhibitor than that administered in step (a) or a treatment that doesnot include the Trk inhibitor of step (a) as a monotherapy to a subjecthaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3); or (c) administeringadditional doses of the Trk inhibitor of step (a) to a subject having acancer cell that does not have at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3). In someembodiments, the different Trk inhibitor is a second Trk inhibitor(e.g., a compound of Table 5 or a pharmaceutically acceptable saltthereof).

Also provided herein are methods of treating a subject having a cancer,that include: (a) administering one or more doses of a first Trkinhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and (c) administering a treatmentincluding one or more doses of a second Trk inhibitor to a subjecthaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3); or (d) administeringadditional doses of the first Trk inhibitor to a subject having a cancercell that does not have at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancer,that include: (a) administering one or more doses of a first Trkinhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and (c) administering a treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, to a subject having a cancer cell that has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more of the amino acid positionsshown in Tables 1, 2, or 3); or (d) administering additional doses ofthe first Trk inhibitor to a subject having a cancer cell that does nothave at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancerthat include: (a) administering one or more doses of a first Trkinhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and (c) administering a treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, and another anticancer agent or anticancertherapy to a subject having a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3); or (d) administering additional doses of the first Trkinhibitor to a subject having a cancer cell that does not have at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancerthat include: (a) determining whether a cancer cell in a sample obtainedfrom a subject having a cancer and previously administered one or moredoses of a first Trk inhibitor has at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3); (b)administering a treatment that includes one or more doses of a secondTrk inhibitor to a subject having a cancer cell that has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more of the amino acid positions shown in Tables 1,2, or 3); or (c) administering additional doses of the first Trkinhibitor to a subject having a cancer cell that does not have at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancerthat include: (a) determining whether a cancer cell in a sample obtainedfrom a subject having a cancer and previously administered one or moredoses of a first Trk inhibitor has at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3); (b)administering a treatment that includes one or more compounds of Table5, or a pharmaceutically acceptable salt thereof, to a subject having acancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3); or (c) administeringadditional doses of the first Trk inhibitor to a subject having a cancercell that does not have at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3).

Also provided herein are methods of treating a subject having a cancer,that include: (a) determining whether a cancer cell in a sample obtainedfrom a subject having a cancer and previously administered one or moredoses of a first Trk inhibitor has at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore of the amino acid positions shown in Tables 1, 2, or 3); (b)administering a treatment that includes one or more compounds of Table5, or a pharmaceutically acceptable salt thereof, and another anticanceragent or anticancer therapy to a subject having a cancer cell that hasat least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); or (c) administering additionaldoses of the first Trk inhibitor to a subject having a cancer cell thatdoes not have at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3).

In some embodiments, the first Trk inhibitor of step (a) is selectedfrom the group consisting of: entrectinib(N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide);(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate; cabozantinib((N-(4-((6,7-Dimethoxyquinolin-4-yl)oxy)phenyl)-N′-(4-fluorophenyl)cyclopropane1,1-dicarboxamide)); dovatinib(4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]quinolin-2(1H)-onemono 2-hydroxypropanoate hydrate); belizatinib(4-fluoro-N-(6-((4-(2-hydroxypropan-2-yl)piperidin-1-yl)methyl)-1-((1s,4s)-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2-yl)benzamide);sitravatinib(N-(3-fluoro-4-((2-(5-(((2-methoxyethyl)amino)methyl)pyridin-2-yl)thieno[3,2-b]pyridin-7-yl)oxy)phenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);PLX7486; altiratinib(N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide);AZD7451((S)—N-(1-(5-fluoropyrimidin-2-yl)ethyl)-3-(5-isopropoxy-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridin-5-amine).For example, the first Trk inhibitor can be entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (or a polymorph thereof).

In some embodiments, a second Trk inhibitor is a compound of Table 5, ora pharmaceutically acceptable salt thereof. For example, the second Trkinhibitor can be selected from the group consisting of:

-   (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   (R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1,1-dimethylurea;-   (R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea;-   (R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-methylurea;-   (R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1-(2-hydroxyethyl)-1-methylurea;-   (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide;    or a pharmaceutically acceptable salt thereof. In some embodiments,    the second Trk inhibitor is selected from the group consisting of:-   (R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   (R)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1,1-dimethylurea;-   (R)—N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazol    o[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   (R)—N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide;-   (R)—N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   or a pharmaceutically acceptable salt thereof. In some embodiments,    the second Trk inhibitor is selected from the group consisting of:-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;    or a pharmaceutically acceptable salt thereof. In some embodiments,    the second Trk inhibitor is selected from the group consisting of:-   (6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]-hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0^(2,6).0^(7,12).0^(22,26)]-hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0^(2,6).0^(7,12).0^(23,27)]-heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;-   (6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),    7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-12-oxa-2,16,20,21,24,26-hexaazapentacyclo[16.5.2.^(17,11).0^(2,6).0^(21,25)]-hexacosa-1(24),    7(26), 8,10,18(25), 19,22-heptaen-17-one;-   1-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),    7,9,11,18(25), 19,22-heptaen-16-yl]ethan-1-one;-   (6R)-9-fluoro-13,16-dioxa-2,11,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]-pentacosa-1(24),    7,9,11,18(25), 19,22-heptaen-17-one;-   (6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R,13    S)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.^(17,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),    18,21-hexaene-16,25-dione;-   (6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1    (25), 7,9,11,19(26),20,23-heptaen-18-one;-   (15S)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17,21,22.25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1    (25),7(12),8,10,19(26),20,23-heptaen-18-one;-   (6R,15S)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1    (24),7,9,11,18(25), 19,22-heptaen-17-one;-   (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;    or a pharmaceutically acceptable salt thereof.

In some embodiments of the methods provided herein, the first Trkinhibitor is entrectinib(N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide);and the second Trk inhibitor is selected from the group consisting of:

-   (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   (R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1,1-dimethylurea;-   (R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea;-   (R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-methylurea;-   (R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1-(2-hydroxyethyl)-1-methylurea;-   (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide;    or a pharmaceutically acceptable salt thereof. In some embodiments    of the methods provided herein, the first Trk inhibitor is    entrectinib    (N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide);    and the second Trk inhibitor is selected from the group consisting    of:-   (R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;

(R)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1,1-dimethylurea;

-   (R)—N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   (R)—N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy-3-methyl    azetidine-1-carboxamide;-   (R)—N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;    or a pharmaceutically acceptable salt thereof. In some embodiments    of the methods provided herein, the first Trk inhibitor is    entrectinib    (N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide);    and the second Trk inhibitor is selected from the group consisting    of:-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;    or a pharmaceutically acceptable salt thereof. In some embodiments    of the methods provided herein, the first Trk inhibitor is    entrectinib    (N-[5-(3,5-difluoro-benzyl)-1H-indazol-3-yl]-4-(4-methylpiperazin-1-yl)-2-(tetrahydro-pyran-4-ylamino)-benzamide);    and the second Trk inhibitor is selected from the group consisting    of:-   (6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12)0.0^(22,26)]-hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0^(2,6).0^(7,12).0^(22,26)]-hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0^(2,6).0^(7,12).0^(23,27)]-heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;-   (6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-12-oxa-2,16,20,21,24,26-hexaazapentacyclo[16.5.2.^(17,11).0^(2,6).0^(21,25)]-hexacosa-1(24),7(26),8,10,18(25),    19,22-heptaen-17-one;-   1-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-16-yl]ethan-1-one;-   (6R)-9-fluoro-13,16-dioxa-2,11,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]-pentacosa-1(24),    7,9,11,18(25), 19,22-heptaen-17-one;-   (6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R,13    S)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.^(17,11).0^(2,6).0^(20,24)]pentacosa-1    (23),7,9,17(24),18,21-hexaene-16,25-dione;-   (6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (15S)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17,21,22.25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen-18-one;-   (6R,15S)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),    7,9,11,18(25), 19,22-heptaen-17-one;-   (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;    or a pharmaceutically acceptable salt thereof.

In some embodiments of the methods provided herein, the first Trkinhibitor is(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate; and the second Trk inhibitor is selected from the groupconsisting of:

-   (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   (R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1,1-di    methylurea;-   (R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea;-   (R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-methylurea;-   (R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1-(2-hydroxyethyl)-1-methylurea;-   (R)—N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide;    or a pharmaceutically acceptable salt thereof. In some embodiments    of the methods provided herein, the first Trk inhibitor is    (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide    sulfate; and the second Trk inhibitor is selected from the group    consisting of:-   (R)—N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   (R)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1,1-dimethylurea;-   (R)—N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;-   (R)—N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide;-   (R)—N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide;    or a pharmaceutically acceptable salt thereof. In some embodiments    of the methods provided herein, the first Trk inhibitor is    (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide    sulfate; and the second Trk inhibitor is selected from the group    consisting of:-   (R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)—N-cyclopropyl-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoro-2-methoxypyridin-3-yl)pyrrolidin-1-yl)-N-methoxypyrazolo[1,5-a]pyrimidine-3-carboxamide;-   (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide;    or a pharmaceutically acceptable salt thereof. In some embodiments    of the methods provided herein, the first Trk inhibitor is    (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide    sulfate; and the second Trk inhibitor is selected from the group    consisting of:-   (6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R,15R)-9-fluoro-15-hydroxy-13-oxa-2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0^(2,6).0^(7,12).0^(23,27)]-heptacosa-1(26),7,9,11,20(27),21,24-heptaen-19-one;-   (6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R)-12-oxa-2,16,20,21,24,26-hexaazapentacyclo[16.5.2.^(17,11).0^(2,6).0^(21,25)]-hexacosa-1(24),7(26),8,10,18(25),19,22-heptaen-17-one;-   1-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-16-yl]ethan-1-one;-   (6R)-9-fluoro-13,16-dioxa-2,11,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;-   (6R)-9,15,15-trifluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).    0^(22,26)]hexacosa-1 (25),7,9,11,19(26),20,23-heptaen-18-one;-   (6R,13    S)-9-fluoro-13-methyl-2,11,15,19,20,23-hexaazapentacyclo[15.5.2.^(17,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),18,21-hexaene-16,25-dione;-   (6R)-9-fluoro-15,15-dimethyl-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one;-   (15S)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17,21,22.25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7(12),    8,10,19(26),20,23-heptaen-18-one;-   (6R,15S)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;-   (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),    19,22-heptaen-17-one;    or a pharmaceutically acceptable salt thereof.

Some examples of these methods further include recording in thesubject's clinical record (e.g., a computer readable medium) that thesubject should be administered a treatment that does not include the Trkinhibitor in step (a) as a monotherapy or a different Trk inhibitor inthe future.

Provided herein are methods of treating a subject having a cancer (e.g.,any of the cancers described herein) that include identifying a subjecthaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3), and administering tothe identified subject a treatment that includes an increased dosage ofa Trk inhibitor (e.g., a first Trk inhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) (e.g., as compared to control dosage of a Trk inhibitor). Asused anywhere herein, a control dosage of a Trk inhibitor is a dosage ofthe Trk inhibitor sufficient to treat a subject having a cancer that isnot a Trk inhibitor-resistant cancer (e.g., a cancer that does notinclude at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3)).

Also provided herein are methods of treating a subject having a cancer(e.g., any of the cancers described herein) and identified as having acancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3), that includeadministering to the identified subject a treatment that includes anincreased dosage of a Trk inhibitor (e.g., a first Trk inhibitor such asentrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) (e.g., as compared to control dosage of a Trk inhibitor).

In some examples, the step of identifying a subject having a cancer cellthat has the at least one point mutation (e.g., any of the pointmutations described herein) in a NTRK1 gene that results in theexpression of a TrkA including a mutation at one or more amino acidposition(s) and/or the at least one point mutation (e.g., any of thepoint mutations described herein) in a NTRK2 gene that results in theexpression of a TrkB including a mutation at one or more amino acidposition(s), and/or the at least one point mutation (e.g., any of thepoint mutations described herein) in a NTRK3 gene that results in theexpression of a TrkC including a mutation at one or more amino acidposition(s), comprises performing an assay to determine the presence ofthe at least one point mutation in a NTRK1 gene and/or the at least onepoint mutation in a NTRK2 gene and/or the at least one point mutation ina NTRK3 gene in a cancer cell in a sample (e.g., a biopsy sample) fromthe subject. Any of the assays described herein can be used to determinethe presence of the at least one point mutation in a NTRK1 gene and/orthe at least one point mutation in a NTRK2 gene and/or the at least onepoint mutation in a NTRK3 gene. In addition, any of the kits providedherein can be used in an assay to determine the presence of the at leastone point mutation in a NTRK1 gene and/or the at least one pointmutation in a NTRK2 gene and/or the at least one point mutation in aNTRK3 gene. In some examples, the assay includes sequencing a segment ofa NTRK1 including the at least one point mutation and/or a segment of aNTRK2 gene including the at least one point mutation and/or a segment ofa NTRK3 gene including the at least one point mutation.

Also provided herein are methods of treating a subject having a cancerthat include (a) administering a control dosage of a Trk inhibitor(e.g., a first Trk inhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) to the subject for a period of time; (b) after (a), determiningwhether a cancer cell in a sample obtained from the subject has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3); and (c) administering an increased dosage of the Trkinhibitor to a subject having a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more of the amino acid positions shown in Tables 1,2, or 3); or (d) administering a control dosage of the Trk inhibitor(e.g., a first Trk inhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) to a subject having a cancer cell that does not have at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more of the amino acid positions shown inTables 1, 2, or 3). As used anywhere herein, a control dosage of a Trkinhibitor is a dosage of the Trk inhibitor sufficient to treat a subjecthaving a cancer that is not a Trk inhibitor-resistant cancer (e.g., acancer that does not include at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3)).

Also provided herein are methods of treating a subject having a cancerthat include: (a) determining whether a cancer cell in a sample obtainedfrom a subject having a cancer and previously administered a controldosage of a Trk inhibitor (e.g., a first Trk inhibitor such asentrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate), has at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); and (b) administering anincreased dosage of the Trk inhibitor to a subject having a cancer cellthat has at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3); or (c) administering a controldosage of the Trk inhibitor to a subject having a cancer cell that doesnot have at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more of the amino acidpositions shown in Tables 1, 2, or 3).

The cancer can be any of the exemplary cancers described herein. In someembodiments, the subject has previously been identified or diagnosed ashaving a cancer. In some examples, the subject has previously beenadministered a treatment for cancer, and the treatment for cancer hasbeen unsuccessful (e.g., high toxicity in the subject or no positiveresponse to the previously administered treatment for cancer).

Some examples of these methods further include recording in thesubject's clinical record (e.g., a computer readable medium) that thesubject should be administered a treatment that includes an increaseddosage of a Trk inhibitor in the future.

Some embodiments of these methods include administering an increaseddosage of the Trk inhibitor in step (b). Some embodiments of thesemethods include administering a control dosage of a Trk inhibitor instep (c).

Some examples of these methods further include recording in thesubject's clinical record (e.g., a computer readable medium) that thesubject should be administered an elevated dosage of the Trk inhibitorin the future. Some examples of these methods further include recordingin the subject's clinical record (e.g., a computer readable medium) thatthe subject should be administered a treatment that does not include aTrk inhibitor as a monotherapy in the future.

In some of the embodiments provided herein, the at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions includes (i) atleast one (e.g., one, two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK1 gene that results in the expression of a TrkA protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid position(s) selected from the group consisting of: 517, 542, 568,573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and 676 (e.g., one ormore of the substitutions of G517R, A542V, V573M, F589L, F589C, G595S,G595R, D596V, F600L, F646V, C656Y, C656F, L657V, G667S, G667C, andY676S), and/or (ii) at least one (e.g., two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen)point mutation in a NTRK2 gene that results in the expression of a TrkBprotein including a mutation at one or more (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) amino acid positions selected from the group consisting of:545, 570, 596, 601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702(e.g., one or more of the substitutions of G545R, A570V, Q596E, Q596P,V601G, F617L, F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F,L683V, G693S, and G713S), and/or (iii) at least one (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK3 gene that results in theexpression of a TrkC protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid position(s) selected from thegroup consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675,685, 686, 696, and 705 (e.g., one or more of the substitutions of G545R,A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A). In someembodiments, the at least one point mutation in a NTRK gene that resultsin the expression of a Trk protein including a mutation at one or moreamino acid positions is selected from a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3.

Methods of Selecting a Treatment for a Subject Having a Cancer

Also provided herein are methods of selecting a treatment that does notinclude a Trk inhibitor (e.g., a first Trk inhibitor such as entrectinibor (S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate) as amonotherapy for a subject having a cancer (e.g., any of the cancersdescribed herein) that include identifying a subject having a cancercell that has at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3), and selecting a treatment thatdoes not include a Trk inhibitor as a monotherapy (e.g., any of thetreatments that do not include a Trk inhibitor as a monotherapydescribed herein) for the identified subject.

Also provided herein are methods of selecting a treatment that does notinclude a Trk inhibitor (e.g., a first Trk inhibitor such as entrectinibor(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) as a monotherapy for a subject having a cancer (e.g., any ofthe treatments that do not include a Trk inhibitor as a monotherapydescribed herein) that include selecting a treatment that does notinclude a Trk inhibitor as a monotherapy (e.g., any of the treatmentsthat do not include a Trk inhibitor as a monotherapy described herein)for a subject identified as having a cancer cell that has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more amino acid positions shown in Table 1, 2, or3).

Some of these methods include selecting a different Trk inhibitor (e.g.,a second Trk inhibitor) or a treatment that does not include the Trkinhibitor of step (a) as a monotherapy to a subject having a cancer cellthat has at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3). In some embodiments, the different Trkinhibitor is a compound of Table 5, or a

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer (e.g., any of the cancers described herein or known inthe art) that include: identifying a subject having a cancer cell thathas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3); and selecting a treatment that includes oneor more compounds of Table 5, or a pharmaceutically acceptable saltthereof, for the identified subject.

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer (e.g., any of the cancers described herein or known inthe art) that include: identifying a subject having a cancer cell thathas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3); and selecting a treatment that includes oneor more compounds of Table 5, or a pharmaceutically acceptable saltthereof, and another anticancer agent (e.g., any one or more of theanticancer agents described herein or known in the art) or anticancertherapy (e.g., any one or more of the anticancer therapies describedherein or known in the art) for the identified subject.

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that include: selecting a treatment that includes one ormore compounds of Table 5, or a pharmaceutically acceptable saltthereof, for a subject identified as having a cancer cell that has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more amino acid positions shown inTable 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that include: selecting a treatment that includes one ormore compounds of Table 5, or a pharmaceutically acceptable saltthereof, and another anticancer agent (e.g., any one or more of theanticancer agents described herein or known in the art) or anticancertherapy (e.g., any one or more of the anticancer therapies describedherein or known in the art) for a subject identified as having a cancercell that has at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that include: (a) administering one or more doses Trkinhibitor (e.g., a first Trk inhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) to the subject for a period of time; (b) after (a), determiningwhether a cancer cell in a sample obtained from the subject has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more amino acid positions shown in Table 1,2, or 3); and (c) selecting a different Trk inhibitor or a treatmentthat does not include the Trk inhibitor of step (a) (e.g.,(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) as a monotherapy for a subject having a cancer cell that has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more amino acid positions shown inTable 1, 2, or 3); or (d) selecting additional doses of the Trkinhibitor of step (a) (e.g.,(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) for a subject having a cancer cell that does not have at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more amino acid positions shown in Table 1,2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that include: (a) determining whether a cancer cell in asample obtained from a subject having a cancer and previouslyadministered one or more doses of a Trk inhibitor (e.g., a first Trkinhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate), has at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3); (b) selecting a different Trkinhibitor or a treatment that does not include the Trk inhibitor of step(a) as a monotherapy for a subject having a cancer cell that has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more amino acid positions shown inTable 1, 2, or 3); or (c) selecting additional doses of the Trkinhibitor of step (a) for a subject having a cancer cell that does nothave at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer, that include: (a) administering one or more doses of afirst Trk inhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3); and (c) selecting a treatment including oneor more doses of a second Trk inhibitor for a subject having a cancercell that has at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3); or (d) selecting additional dosesof the first Trk inhibitor for a subject having a cancer cell that doesnot have at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer, that include: (a) administering one or more doses of afirst Trk inhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3); and (c) selecting a treatment including oneor more compounds of Table 5, or a pharmaceutically acceptable saltthereof, for a subject having a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more amino acid positions shown in Table 1, 2, or 3);or (d) selecting additional doses of the first Trk inhibitor for asubject having a cancer cell that does not have at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more amino acid positions shown in Table 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer, that include: (a) administering one or more doses of afirst Trk inhibitor to the subject for a period of time; (b) after (a),determining whether a cancer cell in a sample obtained from the subjecthas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3); and (c) selecting a treatment including oneor more compounds of Table 5, or a pharmaceutically acceptable saltthereof, and another anticancer agent or anticancer therapy for asubject having a cancer cell that has at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore amino acid positions shown in Table 1, 2, or 3); or (d) selectingadditional doses of the first Trk inhibitor for a subject having acancer cell that does not have at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore amino acid positions shown in Table 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer, that include: (a) determining whether a cancer cell ina sample obtained from a subject having a cancer and previouslyadministered one or more doses of a first Trk inhibitor has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more amino acid positions shown in Table 1, 2, or3); (b) selecting a treatment that includes one or more doses of asecond Trk inhibitor to a subject having a cancer cell that has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more amino acid positions shown in Table 1,2, or 3); or (c) selecting additional doses of the first Trk inhibitorto a subject having a cancer cell that does not have at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more amino acid positions shown in Table 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer, that include: (a) determining whether a cancer cell ina sample obtained from a subject having a cancer and previouslyadministered one or more doses of a first Trk inhibitor has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more amino acid positions shown in Table 1, 2, or3); (b) selecting a treatment that includes one or more compounds ofTable 5, or a pharmaceutically acceptable salt thereof, to a subjecthaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more aminoacid positions shown in Table 1, 2, or 3); or (c) selecting additionaldoses of the first Trk inhibitor to a subject having a cancer cell thatdoes not have at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer, that include: (a) determining whether a cancer cell ina sample obtained from a subject having a cancer and previouslyadministered one or more doses of a first Trk inhibitor has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more amino acid positions shown in Table 1, 2, or3); (b) selecting a treatment that includes one or more compounds ofTable 5, or a pharmaceutically acceptable salt thereof, and an anotheranticancer agent or anticancer therapy to a subject having a cancer cellthat has at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3); or (c) selecting additional doses of thefirst Trk inhibitor to a subject having a cancer cell that does not haveat least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3).

Also provided herein are methods of selecting a treatment that includesan increased dosage of a Trk inhibitor (e.g., a first Trk inhibitor suchas entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) (e.g., as compared to control dosage of a Trk inhibitor) for asubject having a cancer (e.g., any of the cancers described herein) thatinclude identifying a subject having a cancer cell that has at least onepoint mutation in a NTRK gene that results in the expression of a Trkprotein including a mutation at one or more amino acid positions (e.g.,a mutation at one or more amino acid positions shown in Table 1, 2, or3), and selecting an increased dosage of a Trk inhibitor (e.g., ascompared to control dosage of a Trk inhibitor) for the identifiedsubject. As used anywhere herein, a control dosage of a Trk inhibitor isa dosage of the Trk inhibitor sufficient to treat a subject having acancer that is not a Trk inhibitor-resistant cancer (e.g., a cancer thatdoes not include at least one point mutation in a NTRK gene that resultsin the expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3)).

Also provided herein are methods of selecting a treatment that includesan increased dosage of a Trk inhibitor (e.g., a first Trk inhibitor suchas entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) (e.g., as compared to control dosage of a Trk inhibitor) for asubject having a cancer (e.g., any of the cancers described herein) thatinclude selecting a treatment that includes an increased dosage of a Trkinhibitor (e.g., as compared to control dosage of a Trk inhibitor) for asubject identified as having a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more amino acid positions shown in Table 1, 2, or3)).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that include: (a) administering a control dosage of aTrk inhibitor (e.g., a first Trk inhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) to the subject for a period of time; (b) after (a), determiningwhether a cancer cell in a sample obtained from the subject has at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more amino acid positions shown in Table 1,2, or 3); and (c) selecting an increased dosage of the Trk inhibitor fora subject having a cancer cell that has at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore amino acid positions shown in Table 1, 2, or 3); or (d) selecting acontrol dosage of the Trk inhibitor for a subject having a cancer cellthat does not have at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3). As used anywhere herein, a controldosage of a Trk inhibitor is a dosage of the Trk inhibitor sufficient totreat a subject having a cancer that is not a Trk inhibitor-resistantcancer (e.g., a cancer that does not include at least one point mutationin a NTRK gene that results in the expression of a Trk protein includinga mutation at one or more amino acid positions (e.g., a mutation at oneor more amino acid positions shown in Table 1, 2, or 3)).

Also provided herein are methods of selecting a treatment for a subjecthaving a cancer that include: (a) determining whether a cancer cell in asample obtained from a subject having a cancer and previouslyadministered a control dosage of a Trk inhibitor (e.g., a first Trkinhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate), has at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3); (b) selecting an increased dosageof the Trk inhibitor for a subject having a cancer cell that has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more amino acid positions shown inTable 1, 2, or 3); or (c) selecting a control dosage of the Trkinhibitor for a subject having a cancer cell that does not have at leastone point mutation in a NTRK gene that results in the expression of aTrk protein including a mutation at one or more amino acid positions(e.g., a mutation at one or more amino acid positions shown in Table 1,2, or 3).

Some examples of these methods further include administering theselected treatment to the identified subject. In some examples, theselected treatment is self-administered. In other examples, the selectedtreatment is administered by a medical professional (e.g., any of themedical professionals described herein). Some examples of these methodsfurther include recording the selected treatment in the identifiedsubject's clinical record (e.g., a computer readable medium).

In some of the embodiments provided herein, the at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions includes (i) atleast one (e.g., one, two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK1 gene that results in the expression of a TrkA protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid position(s) selected from the group consisting of: 517, 542, 568,573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and 676 (e.g., one ormore of the substitutions of G517R, A542V, V573M, F589L, F589C, G595S,G595R, D596V, F600L, F646V, C656Y, C656F, L657V, G667S, G667C, andY676S), and/or (ii) at least one (e.g., two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen)point mutation in a NTRK2 gene that results in the expression of a TrkBprotein including a mutation at one or more (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) amino acid positions selected from the group consisting of:545, 570, 596, 601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702(e.g., one or more of the substitutions of G545R, A570V, Q596E, Q596P,V601G, F617L, F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F,L683V, G693S, and G713S), and/or (iii) at least one (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK3 gene that results in theexpression of a TrkC protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid position(s) selected from thegroup consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675,685, 686, 696, and 705 (e.g., one or more of the substitutions of G545R,A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A). In someembodiments, the at least one point mutation in a NTRK gene that resultsin the expression of a Trk protein including a mutation at one or moreamino acid positions is selected from a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3.

Methods of Selecting a Subject Having a Cancer for Treatment

Also provided herein are methods of selecting a subject having a cancerfor a treatment that does not include a Trk inhibitor (e.g., a first Trkinhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) as a monotherapy that include identifying a subject as having acancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3), and selecting the identifiedsubject for a treatment that does not include a Trk inhibitor as amonotherapy (e.g., any of the treatments that do not include a Trkinhibitor as a monotherapy described herein).

Also provided herein are methods of selecting a subject having a cancerfor a treatment that does not include a Trk inhibitor (e.g., a first Trkinhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) as a monotherapy that include selecting a subject having acancer (e.g., any of the cancers described herein) and identified ashaving a cancer cell that has at least one point mutation in a NTRK genethat results in the expression of a Trk protein including a mutation atone or more amino acid positions (e.g., a mutation at one or more aminoacid positions shown in Table 1, 2, or 3), for a treatment that does notinclude a Trk inhibitor as a monotherapy (e.g., any of the treatmentsthat do not include a Trk inhibitor as a monotherapy described herein).

In some examples, the treatment that does not include a Trk inhibitor asa monotherapy includes one or more of: surgery (e.g., open surgery orminimally invasive surgery), radiation therapy (e.g., external beamradiation therapy or internal radiation therapy), chemotherapy (e.g., analkylating agent, antimetabolites, anti-microtubule agents,topoisomerase inhibitors, and cytotoxic antibiotics), immunotherapy(e.g., adoptive cell transfer, a cytokine, a cancer vaccine, andBacillus Calmette-Guérom), hormone therapy (e.g., a drug that blocksestrogen, a drug that lowers estrogen levels, a progesterone-like drug,or an anti-androgen drug), small molecule drugs targeting other kinasesin a Trk-signaling pathway, recombinant antibodies (e.g., any ofexemplary recombinant antibodies described herein, e.g., anti-NGFantibodies), and stem cell transplant. In some examples, the treatmentthat does not include a Trk inhibitor as a monotherapy can be, e.g., atreatment that includes (i) one or more of surgery, radiation therapy,chemotherapy, immunotherapy, hormone therapy, small molecule drugstargeting other kinases in a Trk-signaling pathway, recombinantantibodies, and stem cell transplant, and (ii) one or more Trkinhibitors (e.g., any of the Trk inhibitors described herein). In someembodiments, the treatment that does not include a Trk inhibitor as amonotherapy can be, e.g., a treatment that includes two or more Trkinhibitors (e.g., any of the Trk inhibitors described herein).Additional examples of treatments that do not include a Trk inhibitor asa monotherapy, and doses and routes of administration of the same, aredescribed herein or known in the art.

Some examples of these methods further include administering a treatmentthat does not include a Trk inhibitor as a monotherapy (e.g., using anyof the treatments that do not include a Trk inhibitor as a monotherapy,any of the routes of administration, any of the doses, and/or any of thefrequencies of administration described herein) to the selected subject.In some examples, the treatment that does not include a Trk inhibitor asa monotherapy is self-administered. In other examples, the treatmentthat does not include a Trk inhibitor as a monotherapy is administeredto the selected subject by a medical professional. In some examples, theselected subject is hospitalized. In other examples, the subject isadministered the treatment that does not include a Trk inhibitor as amonotherapy, on an outpatient basis. Some methods further includerecording in the subject's clinical record (e.g., a computer readablemedium) that the subject is selected for a treatment that does notinclude a Trk inhibitor as a monotherapy.

Also provided herein are methods of selecting a subject having a cancerfor a treatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, that include: identifying asubject having a cancer cell that has at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore amino acid positions shown in Table 1, 2, or 3); and selecting theidentified subject for a treatment that includes one or more compoundsof Table 5, or a pharmaceutically acceptable salt thereof.

Also provided herein are methods of selecting a subject having a cancerfor a treatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, and another anticancer agent(e.g., any one or more of the another anticancer agents described hereinor known in the art) or another anticancer therapy that include:identifying a subject having a cancer cell that has at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions (e.g., amutation at one or more amino acid positions shown in Table 1, 2, or 3);and selecting the identified subject for a treatment that includes oneor more compounds of Table 5, or a pharmaceutically acceptable saltthereof, and another anticancer agent or anticancer therapy.

Also provided herein are methods of selecting a subject having a cancerfor a treatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, that include: identifying asubject having a cancer cell that has at least one point mutation in aNTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore amino acid positions shown in Table 1, 2, or 3); and selecting theidentified subject for a treatment that includes one or more compoundsof Table 5, or a pharmaceutically acceptable salt thereof.

Also provided herein are methods of selecting a subject having a cancerfor a treatment that includes one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, and another anticancer agentor anticancer therapy that include: identifying a subject having acancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3); and selecting the identifiedsubject for a treatment that includes one or more compounds of Table 5,or a pharmaceutically acceptable salt thereof, and another anticanceragent or anticancer therapy.

Some examples of these methods further include administering a treatmentthat includes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, or a treatment that includes one or morecompounds of Table 5, or a pharmaceutically acceptable salt thereof, andanother anticancer agent or anticancer therapy to the selected subject.

In some of the embodiments provided herein, the at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions includes (i) atleast one (e.g., one, two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK1 gene that results in the expression of a TrkA protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid position(s) selected from the group consisting of: 517, 542, 568,573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and 676 (e.g., one ormore of the substitutions of G517R, A542V, V573M, F589L, F589C, G595S,G595R, D596V, F600L, F646V, C656Y, C656F, L657V, G667S, G667C, andY676S), and/or (ii) at least one (e.g., two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen)point mutation in a NTRK2 gene that results in the expression of a TrkBprotein including a mutation at one or more (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) amino acid positions selected from the group consisting of:545, 570, 596, 601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702(e.g., one or more of the substitutions of G545R, A570V, Q596E, Q596P,V601G, F617L, F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F,L683V, G693S, and G713S), and/or (iii) at least one (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK3 gene that results in theexpression of a TrkC protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid position(s) selected from thegroup consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675,685, 686, 696, and 705 (e.g., one or more of the substitutions of G545R,A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A). In someembodiments, the at least one point mutation in a NTRK gene that resultsin the expression of a Trk protein including a mutation at one or moreamino acid positions is selected from a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3.

Methods of Determining the Likelihood that a Subject Having a CancerWill have a Positive Response to a Treatment with a Trk Inhibitor as aMonotherapy

Also provided herein are methods of determining the likelihood that asubject having a cancer (e.g., any of the cancers described herein) willhave a positive response to a treatment with a Trk inhibitor (e.g., afirst Trk inhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrrolidine-1-carboxamidesulfate) as a monotherapy that include determining whether a cancer cellin a sample obtained from the subject has at least one point mutation ina NTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore amino acid positions shown in Table 1, 2, or 3), has a decreasedlikelihood of having a positive response to a treatment with a Trkinhibitor as a monotherapy (e.g., as compared to a subject having acancer cell that does not have at least one point mutation in a NTRKgene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore amino acid positions shown in Table 1, 2, or 3)).

Also provided herein are methods of determining the likelihood that asubject having cancer (e.g., any of the cancers described herein) willhave a positive response to a treatment with a Trk inhibitor (e.g., afirst Trk inhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) as a monotherapy that include determining that a subject havinga cancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3), has a decreased likelihood ofhaving a positive response to treatment with a Trk inhibitor as amonotherapy (e.g., as compared to a subject having a cancer cell thatdoes not have at least one point mutation in a NTRK gene that results inthe expression of a Trk protein including a mutation at one or moreamino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3)).

Some examples of these methods include administering a treatment thatdoes not include a Trk inhibitor as a monotherapy (e.g., any of thetreatments that do not include a Trk inhibitor as a monotherapydescribed herein) to a subject determined to have a decreased likelihoodof having a positive response to treatment with a Trk inhibitor as amonotherapy.

In some examples, the treatment that does not include a Trk inhibitor asa monotherapy includes one or more of: surgery (e.g., open surgery orminimally invasive surgery), radiation therapy (e.g., external beamradiation therapy or internal radiation therapy), chemotherapy (e.g., analkylating agent, antimetabolites, anti-microtubule agents,topoisomerase inhibitors, and cytotoxic antibiotics), immunotherapy(e.g., adoptive cell transfer, a cytokine, a cancer vaccine, andBacillus Calmette-Guérom), hormone therapy (e.g., a drug that blocksestrogen, a drug that lowers estrogen levels, a progesterone-like drug,or an anti-androgen drug), small molecule drugs targeting other kinasesin a Trk-signaling pathway, recombinant antibodies (e.g., any ofexemplary recombinant antibodies described herein, e.g., anti-NGFantibodies), and stem cell transplant. In some examples, the treatmentthat does not include a Trk inhibitor as a monotherapy can be, e.g., atreatment that includes (i) one or more of surgery, radiation therapy,chemotherapy, immunotherapy, hormone therapy, small molecule drugstargeting other kinases in a Trk-signaling pathway, recombinantantibodies, and stem cell transplant, and (ii) one or more Trkinhibitors (e.g., any of the Trk inhibitors described herein). In someembodiments, the treatment that does not include a Trk inhibitor as amonotherapy can be, e.g., a treatment that includes two or more Trkinhibitors (e.g., any of the Trk inhibitors described herein).Additional examples of treatments that do not include a Trk inhibitor asa monotherapy, and doses and routes of administration of the same, aredescribed herein or known in the art.

In some examples, the treatment that does not include a Trk inhibitor asa monotherapy is self-administered. In other examples, the treatmentthat does not include a Trk inhibitor as a monotherapy is administeredto the subject by a medical professional. In some examples, the subjectis hospitalized. In other examples, the subject is administered thetreatment that does not include a Trk inhibitor as a monotherapy, on anoutpatient basis. Some methods further include recording in thesubject's clinical record (e.g., a computer readable medium) that thesubject has a decreased likelihood of having a positive response totreatment with a Trk inhibitor as a monotherapy.

Also provided herein are methods of determining the likelihood that asubject having a cancer will have a positive response to treatment thatincludes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, that include: determining whether a cancer cellin a sample obtained from the subject has at least one point mutation ina NTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore amino acid positions shown in Table 1, 2, or 3), has an increasedlikelihood of having a positive response to treatment that includes oneor more compounds of Table 5, or a pharmaceutically acceptable saltthereof.

Also provided herein are methods of determining the likelihood that asubject having cancer will have a positive response to treatment thatincludes one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, that include: determining that a subject havinga cancer cell that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3), has an increased likelihood ofhaving a positive response to treatment including one or more compoundsof Table 5, or a pharmaceutically acceptable salt thereof.

In some of the embodiments provided herein, the at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions includes (i) atleast one (e.g., one, two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK1 gene that results in the expression of a TrkA protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid position(s) selected from the group consisting of: 517, 542, 568,573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and 676 (e.g., one ormore of the substitutions of G517R, A542V, V573M, F589L, F589C, G595S,G595R, D596V, F600L, F646V, C656Y, C656F, L657V, G667S, G667C, andY676S), and/or (ii) at least one (e.g., two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen)point mutation in a NTRK2 gene that results in the expression of a TrkBprotein including a mutation at one or more (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) amino acid positions selected from the group consisting of:545, 570, 596, 601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702(e.g., one or more of the substitutions of G545R, A570V, Q596E, Q596P,V601G, F617L, F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F,L683V, G693S, and G713S), and/or (iii) at least one (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK3 gene that results in theexpression of a TrkC protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid position(s) selected from thegroup consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675,685, 686, 696, and 705 (e.g., one or more of the substitutions of G545R,A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A). In someembodiments, the at least one point mutation in a NTRK gene that resultsin the expression of a Trk protein including a mutation at one or moreamino acid positions is selected from a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3.

Methods of Predicting the Efficacy of Treatment with a Trk Inhibitor asa Monotherapy in a Subject Having Cancer

Also provided herein are methods of predicting the efficacy of treatmentwith a Trk inhibitor (e.g., a first Trk inhibitor such as entrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) as a monotherapy in a subject having cancer (e.g., any of thecancers described herein) that include determining whether a cancer cellin a sample obtained from the subject has at least one point mutation ina NTRK gene that results in the expression of a Trk protein including amutation at one or more amino acid positions (e.g., a mutation at one ormore amino acid positions shown in Table 1, 2, or 3), and determiningthat a treatment with a Trk inhibitor as a monotherapy is less likely tobe effective in a subject having a cancer cell in a sample obtained fromthe subject that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3) (e.g., as compared to a subjecthaving a cancer cell in a sample obtained from the subject that does nothave at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3)).

Also provided herein are methods of predicting the efficacy of atreatment with a Trk inhibitor (e.g., a first Trk inhibitor such asentrectinib or(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate) as a monotherapy in a subject having a cancer (e.g., any of thecancers described herein) that include determining that treatment with aTrk inhibitor as a monotherapy is less likely to be effective in asubject having a cancer cell in a sample obtained from the subject thathas at least one point mutation in a NTRK gene that results in theexpression of a Trk protein including a mutation at one or more aminoacid positions (e.g., a mutation at one or more amino acid positionsshown in Table 1, 2, or 3) (e.g., as compared to a subject having acancer cell in a sample obtained from the subject that does not have atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more amino acid positions shown inTable 1, 2, or 3)).

Some methods further include recording in the subject's clinical record(e.g., a computer readable medium) the predicted efficacy of a treatmentwith a Trk inhibitor as a monotherapy, in the subject having a cancer.Some examples of these methods further include selecting a treatmentthat does not include a Trk inhibitor as a monotherapy for the subject.Some examples further include administering the selected treatment tothe subject (e.g., using any of the treatments that do not include a Trkinhibitor as a monotherapy, any of the routes of administration, any ofthe doses, and/or any of the frequencies of administration describedherein).

In some examples, the treatment that does not include a Trk inhibitor asa monotherapy includes one or more of: surgery (e.g., open surgery orminimally invasive surgery), radiation therapy (e.g., external beamradiation therapy or internal radiation therapy), chemotherapy (e.g., analkylating agent, antimetabolites, anti-microtubule agents,topoisomerase inhibitors, and cytotoxic antibiotics), immunotherapy(e.g., adoptive cell transfer, a cytokine, a cancer vaccine, andBacillus Calmette-Guérom), hormone therapy (e.g., a drug that blocksestrogen, a drug that lowers estrogen levels, a progesterone-like drug,or an anti-androgen drug), small molecule drugs targeting other kinasesin a Trk-signaling pathway, recombinant antibodies (e.g., any ofexemplary recombinant antibodies described herein, e.g., anti-NGFantibodies), and stem cell transplant. In some examples, the treatmentthat does not include a Trk inhibitor as a monotherapy can be, e.g., atreatment that includes (i) one or more of surgery, radiation therapy,chemotherapy, immunotherapy, hormone therapy, small molecule drugstargeting other kinases in a Trk-signaling pathway, recombinantantibodies, and stem cell transplant, and (ii) one or more Trkinhibitors (e.g., any of the Trk inhibitors described herein). In someembodiments, the treatment that does not include a Trk inhibitor as amonotherapy can be, e.g., a treatment that includes two or more Trkinhibitors (e.g., any of the Trk inhibitors described herein).Additional examples of treatments that do not include a Trk inhibitor asa monotherapy, and doses and routes of administration of the same, aredescribed herein or known in the art.

In some examples, the treatment that does not include a Trk inhibitor asa monotherapy is self-administered. In other examples, the treatmentthat does not include a Trk inhibitor as a monotherapy is administeredto the subject by a medical professional. In some examples, the subjectis hospitalized. In other examples, the subject is administered thetreatment that does not include a Trk inhibitor as a monotherapy, on anoutpatient basis.

Also provided herein are methods of predicting the efficacy of treatmentwith a treatment including one or more compounds of Table 5, or apharmaceutically acceptable salt thereof, in a subject having cancer,that include: determining whether a cancer cell in a sample obtainedfrom the subject has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3); and determining that treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, is more likely to be effective in a subjecthaving a cancer cell in a sample obtained from the subject that has atleast one point mutation in a NTRK gene that results in the expressionof a Trk protein including a mutation at one or more amino acidpositions (e.g., a mutation at one or more amino acid positions shown inTable 1, 2, or 3).

Also provided herein are methods of predicting the efficacy of treatmentincluding one or more compounds of Table 5, or a pharmaceuticallyacceptable salt thereof, in a subject having cancer, that include:determining that treatment including one or more compounds of Table 5,or a pharmaceutically acceptable salt thereof, is more likely to beeffective in a subject having a cancer cell in a sample obtained fromthe subject that has at least one point mutation in a NTRK gene thatresults in the expression of a Trk protein including a mutation at oneor more amino acid positions (e.g., a mutation at one or more amino acidpositions shown in Table 1, 2, or 3).

In some of the embodiments provided herein, the at least one pointmutation in a NTRK gene that results in the expression of a Trk proteinincluding a mutation at one or more amino acid positions includes (i) atleast one (e.g., one, two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK1 gene that results in the expression of a TrkA protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid position(s) selected from the group consisting of: 517, 542, 568,573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and 676 (e.g., one ormore of the substitutions of G517R, A542V, V573M, F589L, F589C, G595S,G595R, D596V, F600L, F646V, C656Y, C656F, L657V, G667S, G667C, andY676S), and/or (ii) at least one (e.g., two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen)point mutation in a NTRK2 gene that results in the expression of a TrkBprotein including a mutation at one or more (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) amino acid positions selected from the group consisting of:545, 570, 596, 601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702(e.g., one or more of the substitutions of G545R, A570V, Q596E, Q596P,V601G; F617L, F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F,L683V, G693S, and G713S), and/or (iii) at least one (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK3 gene that results in theexpression of a TrkC protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid position(s) selected from thegroup consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675,685, 686, 696, and 705 (e.g., one or more of the substitutions of G545R,A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A). In someembodiments, the at least one point mutation in a NTRK gene that resultsin the expression of a Trk protein including a mutation at one or moreamino acid positions is selected from a mutation at one or more of theamino acid positions shown in Tables 1, 2, or 3.

Methods of Predicting a Subject's Risk for Developing a TrkInhibitor-Resistant Cancer

Also provided herein are methods of identifying a determining asubject's risk for developing a Trk inhibitor-resistant cancer (e.g.,any of the cancers described herein) that include determining whether acell in a sample obtained from the subject has (i) at least one (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) point mutation in a NTRK1 gene thatresults in the expression of a TrkA protein including a mutation at oneor more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid position(s)selected from the group consisting of: 517, 542, 568, 573, 589, 595,599, 600, 602, 646, 656, 657, 667, and 676 (e.g., one or more of thesubstitutions of G517R, A542V, V573M, F589L, F589C, G595S, G595R, D596V,F600L, F646V, C656Y, C656F, L657V, G667S, G667C, and Y676S) and/or (ii)at least one (e.g., two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK2 gene that results in the expression of a TrkB protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid positions selected from the group consisting of: 545, 570, 596,601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702 (e.g., one ormore of the substitutions of G545R, A570V, Q596E, Q596P, V601G, F617L,F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S,and G713S), and/or (iii) at least one (e.g., two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, orfifteen) point mutation in a NTRK3 gene that results in the expressionof a TrkC protein including a mutation at one or more (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) amino acid position(s) selected from the groupconsisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685,686, 696, and 705 (e.g., one or more of the substitutions of G545R,A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A), andidentifying a subject having a cell that has (i) at least one (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) point mutation in a NTRK1 gene thatresults in the expression of a TrkA protein including a mutation at oneor more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid position(s)selected from the group consisting of: 517, 542, 568, 573, 589, 595,599, 600, 602, 646, 656, 657, 667, and 676 (e.g., one or more of thesubstitutions of G517R, A542V, V573M, F589L, F589C, G595S, G595R, D596V,F600L, F646V, C656Y, C656F, L657V, G667S, G667C, and Y676S), and/or (ii)at least one (e.g., two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK2 gene that results in the expression of a TrkB protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid positions selected from the group consisting of: 545, 570, 596,601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702 (e.g., one ormore of the substitutions of G545R, A570V, Q596E, Q596P, V601G, F617L,F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S,and G713S), and/or (iii) at least one (e.g., two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, orfifteen) point mutation in a NTRK3 gene that results in the expressionof a TrkC protein including a mutation at one or more (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) amino acid position(s) selected from the groupconsisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685,686, 696, and 705 (e.g., one or more of the substitutions of G545R,A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A), as havingan increased likelihood of developing a Trk inhibitor-resistant cancer(e.g., as compared to a subject not having (i) a point mutation in aNTRK1 gene that results in the expression of a TrkA protein including amutation at one or more amino acid position(s) selected from the groupconsisting of: 517, 542, 568, 573, 589, 595, 599, 600, 602, 646, 656,657, 667, and 676 (e.g., one or more of the substitutions of G517R,A542V, V573M, F589L, F589C, G595S, G595R, D596V, F600L, F646V, C656Y,C656F, L657V, G667S, G667C, and Y676S), or (ii) a point mutation in aNTRK2 gene that results in the expression of a TrkB protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid positions selected from the group consisting of: 545, 570, 596,601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702 (e.g., one ormore of the substitutions of G545R, A570V, Q596E, Q596P, V601G, F617L,F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S,and G713S), or (iii) a point mutation in a NTRK3 gene that results inthe expression of a TrkC protein including a mutation at one or moreamino acid position(s) selected from the group consisting of: 545, 570,596, 601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and 705 (e.g.,one or more substitutions of G545R, A570V, F617L, G623R, D624V, C685Y,C685F, L686V, and G696A)).

Also provided herein are methods of determining a subject's risk fordeveloping a Trk inhibitor-resistant cancer (e.g., any of the cancersdescribed herein) that include identifying a subject having a cell thathas (i) at least one (e.g., two, three, four, five, six, seven, eight,nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) pointmutation(s) in a NTRK1 gene that results in the expression of a TrkAprotein including a mutation at one or more (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) amino acid position(s) selected from the group consistingof: 517, 542, 568, 573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and676 (e.g., one or more of the substitutions of G517R, A542V, V573M,F589L, F589C, G595S, G595R, D596V, F600L, F646V, C656Y, C656F, L657V,G667S, G667C, and Y676S), and/or (ii) at least one (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK2 gene that results in theexpression of a TrkB protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid positions selected from thegroup consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 672,682, 683, 693, and 702 (e.g., one or more of the substitutions of G545R,A570V, Q596E, Q596P, V601G, F617L, F617C, F617I, G623S, G623R, D624V,R630K, C682Y, C682F, L683V, G693S, and G713S), and/or (iii) at least one(e.g., two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, or fifteen) point mutation in a NTRK3 genethat results in the expression of a TrkC protein including a mutation atone or more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid position(s)selected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 675, 685, 686, 696, and 705 (e.g., one or more of thesubstitutions of G545R, A570V, F617L, G623R, D624V, C685Y, C685F, L686V,and G696A), as having an increased likelihood of developing a Trkinhibitor-resistant cancer (e.g., as compared to a subject having a cellthat does not have (i) a point mutation in a NTRK1 gene that results inthe expression of a TrkA protein including a mutation at one or moreamino acid position(s) selected from the group consisting of: 517, 542,568, 573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and 676 (e.g.,one or more of the substitutions of G517R, A542V, V573M, F589L, F589C,G595S, G595R, D596V, F600L, F646V, C656Y, C656F, L657V, G667S, G667C,and Y676S), or (ii) a point mutation in a NTRK2 gene that results in theexpression of a TrkB protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid positions selected from thegroup consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 672,682, 683, 693, and 702 (e.g., one or more of the substitutions of G545R,A570V, Q596E, Q596P, V601G, F617L, F617C, F617I, G623S, G623R, D624V,R630K, C682Y, C682F, L683V, G693S, and G713S), or (iii) a point mutationin a NTRK3 gene that results in the expression of a TrkC proteinincluding a mutation at one or more amino acid position(s) selected fromthe group consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630,675, 685, 686, 696, and 705 (e.g., one or more of the substitutions ofG545R, A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A)).

Some methods further include recording in the subject's clinical record(e.g., a computer readable medium) the subject's risk of developing aTrk inhibitor-resistant cancer. The Trk inhibitor-resistant cancer canbe any of the exemplary cancers described herein. Some methods furtherinclude periodic testing for the presence of a Trk inhibitor-resistantcancer in the subject.

In some examples, the subject is identified as having been exposed to asignificant level of carcinogen(s) (e.g., tobacco smoke, UVB radiation,and gamma irradiation). In some examples, the subject is suspected ofhaving cancer, presents with one or more symptoms of cancer (e.g., anyof the symptoms of cancer described herein), and/or has a family historyof cancer.

In some examples, the step of determining whether a cancer cell in asample obtained from the subject has (i) at least one (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK1 gene that results in theexpression of a TrkA protein including one or more (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) mutations (e.g., any of the mutations in TrkAdescribed herein), and/or (ii) at least one (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) point mutation in a NTRK2 gene that results in theexpression of a TrkB protein including one or more (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) mutations (e.g., any of the mutations in TrkBdescribed herein), and/or (iii) at least one (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) point mutation in a NTRK3 gene that results in theexpression of a TrkC protein including one or more (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) mutations (e.g., any of the mutations in TrkCdescribed herein), comprises performing an assay to determine thepresence of the at least one point mutation in a NTRK1 gene and/or theat least one point mutation in a NTRK2 gene and/or the at least onepoint mutation in a NTRK3 gene in a cancer cell in the sample (e.g., abiopsy sample) from the subject. Any of the assays described herein canbe used to determine the presence of the at least one point mutation ina NTRK1 gene and/or the at least one point mutation in a NTRK2 geneand/or the at least one point mutation in a NTRK3 gene. In addition, anyof the kits provided herein can be used in an assay to determine thepresence of the at least one point mutation in a NTRK1 gene and/or theat least one point mutation in a NTRK2 gene and/or the at least onepoint mutation in a NTRK3 gene. In some examples, the assay includessequencing a segment of a NTRK1 gene including the at least one pointmutation and/or a segment of a NTRK2 gene including the at least onepoint mutation and/or a segment of a NTRK3 gene including the at leastone point mutation.

Methods of Determining the Presence of a Trk Inhibitor-Resistant Cancerin a Subject

Also provided herein are methods of determining the presence of a Trkinhibitor-resistant cancer (e.g., any of the cancers described herein)in a subject that include determining whether a cell in a sampleobtained from the subject has (i) at least one (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) point mutation in a NTRK1 gene that results in theexpression of a TrkA protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid position(s) selected from thegroup consisting of: 517, 542, 568, 573, 589, 595, 599, 600, 602, 646,656, 657, 667, and 676 (e.g., one or more of the substitutions of G517R,A542V, V573M, F589L, F589C, G595S, G595R, D596V, F600L, F646V, C656Y,C656F, L657V, G667S, G667C, and Y676S), and/or (ii) at least one (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) point mutation in a NTRK2 gene thatresults in the expression of a TrkB protein including a mutation at oneor more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid positionsselected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 672, 682, 683, 693, and 702 (e.g., one or more of thesubstitutions of G545R, A570V, Q596E, Q596P, V601G, F617L, F617C, F617I,G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S, and G713S),and/or (iii) at least one (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) pointmutation in a NTRK3 gene that results in the expression of a TrkCprotein including a mutation at one or more (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) amino acid position(s) selected from the group consistingof: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and705 (e.g., one or more of the substitutions of G545R, A570V, F617L,G623R, D624V, C685Y, C685F, L686V, and G696A), and determining that asubject having a cell that has (i) at least one (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) point mutation in a NTRK1 gene that results in theexpression of a TrkA protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid position(s) selected from thegroup consisting of: 517, 542, 568, 573, 589, 595, 599, 600, 602, 646,656, 657, 667, and 676 (e.g., one or more of the substitutions of G517R,A542V, V573M, F589L, F589C, G595S, G595R, D596V, F600L, F646V, C656Y,C656F, L657V, G667S, G667C, and Y676S), and/or (ii) at least one (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) point mutation in a NTRK2 gene thatresults in the expression of a TrkB protein including a mutation at oneor more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid positionsselected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 672, 682, 683, 693, and 702 (e.g., one or more of thesubstitutions of G545R, A570V, Q596E, Q596P, V601G, F617L, F617C, F617I,G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S, and G713S),and/or (iii) at least one (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) pointmutation in a NTRK3 gene that results in the expression of a TrkCprotein including a mutation at one or more (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) amino acid position(s) selected from the group consistingof: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and705 (e.g., one or more of the substitutions of G545R, A570V, F617L,G623R, D624V, C685Y, C685F, L686V, and G696A), has a Trkinhibitor-resistant cancer.

Also provided herein are methods of determining the presence of a Trkinhibitor-resistant cancer (e.g., any of the cancers described herein)in a subject that include determining that a subject having a cell thathas (i) at least one (e.g., two, three, four, five, six, seven, eight,nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) pointmutation in a NTRK1 gene that results in the expression of a TrkAprotein including a mutation at one or more (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) amino acid position(s) selected from the group consistingof: 517, 542, 568, 573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and676 (e.g., one or more of the substitutions of G517R, A542V, V573M,F589L, F589C, G595S, G595R, D596V, F600L, F646V, C656Y, C656F, L657V,G667S, G667C, and Y676S), and/or (ii) at least one (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK2 gene that results in theexpression of a TrkB protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid positions selected from thegroup consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 672,682, 683, 693, and 702 (e.g., one or more of the substitutions of G545R,A570V, Q596E, Q596P, V601G; F617L, F617C, F617I, G623S, G623R, D624V,R630K, C682Y, C682F, L683V, G693S, and G713S), and/or (iii) at least one(e.g., two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, or fifteen) point mutation in a NTRK3 genethat results in the expression of a TrkC protein including a mutation atone or more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid position(s)selected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 675, 685, 686, 696, and 705 (e.g., one or more of thesubstitutions of G545R, A570V, F617L, G623R, D624V, C685Y, C685F, L686V,and G696A), has a Trk inhibitor-resistant cancer (e.g., as compared to asubject having a cell that does not have (i) a point mutation in a NTRK1gene that results in the expression of a TrkA protein including amutation at one or more amino acid position(s) selected from the groupconsisting of: 517, 542, 568, 573, 589, 595, 599, 600, 602, 646, 656,657, 667, and 676 (e.g., one or more of the substitutions of G517R,A542V, V573M, F589L, F589C, G595S, G595R, D596V, F600L, F646V, C656Y,C656F, L657V, G667S, G667C, and Y676S), or (ii) a point mutation in aNTRK2 gene that results in the expression of a TrkB protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid positions selected from the group consisting of: 545, 570, 596,601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702 (e.g., one ormore of the substitutions of G545R, A570V, Q596E, Q596P, V601G; F617L,F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S,and G713S), or (iii) a point mutation in a NTRK3 gene that results inthe expression of a TrkC protein including a mutation at one or more(e.g., two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, or fifteen) amino acid position(s) selectedfrom the group consisting of: 545, 570, 596, 601, 617, 623, 624, 628,630, 675, 685, 686, 696, and 705 (e.g., one or more of the substitutionsof G545R, A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A)).

Some embodiments further include confirming a diagnosis of a Trkinhibitor-resistant cancer in the subject. Confirming the diagnosis of aTrk inhibitor-resistant cancer in a subject can include, e.g.,performing additional laboratory tests (e.g., urine or blood tests,e.g., complete blood count), imaging tests (e.g., computerizedtomography (CT), bone scan, magnetic resonance imaging (MRI), positronemission tomography (PET) scan, ultrasound, and X-ray), and/or physicalexamination, e.g., before and after administration of a treatment with aTrk inhibitor as a monotherapy.

Some methods further include recording in the subject's clinical record(e.g., a computer readable medium) that the subject has a Trkinhibitor-resistant cancer. The cancer can be any of the exemplarycancers described herein.

Some examples further includes administering a treatment that does notinclude a Trk inhibitor as a monotherapy (e.g., any of the treatmentsthat do not include a Trk inhibitor as a monotherapy described herein).In some examples, the treatment that does not include a Trk inhibitor asa monotherapy includes one or more of: surgery (e.g., open surgery orminimally invasive surgery), radiation therapy (e.g., external beamradiation therapy or internal radiation therapy), chemotherapy (e.g., analkylating agent, antimetabolites, anti-microtubule agents,topoisomerase inhibitors, and cytotoxic antibiotics), immunotherapy(e.g., adoptive cell transfer, a cytokine, a cancer vaccine, andBacillus Calmette-Guérom), hormone therapy (e.g., a drug that blocksestrogen, a drug that lowers estrogen levels, a progesterone-like drug,or an anti-androgen drug), small molecule drugs targeting other kinasesin a Trk-signaling pathway, recombinant antibodies (e.g., any ofexemplary recombinant antibodies described herein, e.g., anti-NGFantibodies), and stem cell transplant. In some examples, the treatmentthat does not include a Trk inhibitor as a monotherapy can be, e.g., atreatment that includes (i) one or more of surgery, radiation therapy,chemotherapy, immunotherapy, hormone therapy, small molecule drugstargeting other kinases in a Trk-signaling pathway, recombinantantibodies, and stem cell transplant, and (ii) one or more Trkinhibitors (e.g., any of the Trk inhibitors described herein). In someembodiments, the treatment that does not include a Trk inhibitor as amonotherapy can be, e.g., a treatment that includes two or more Trkinhibitors (e.g., any of the Trk inhibitors described herein).Additional examples of treatments that do not include a Trk inhibitor asa monotherapy, and doses and routes of administration of the same, aredescribed herein or known in the art.

In some examples, the treatment that does not include a Trk inhibitor asa monotherapy is self-administered. In other examples, the treatmentthat does not include a Trk inhibitor as a monotherapy is administeredto the subject by a medical professional. In some examples, the subjectis hospitalized. In other examples, the subject is administered thetreatment that does not include a Trk inhibitor as a monotherapy, on anoutpatient basis.

In some examples, the subject is identified as having been exposed to asignificant level of carcinogen(s) (e.g., tobacco smoke, UVB radiation,and gamma irradiation). In some examples, the subject is suspected ofhaving cancer, presents with one or more symptoms of cancer (e.g., anyof the symptoms of cancer described herein), and/or has a family historyof cancer.

In some examples, the step of determining whether a cancer cell in asample obtained from the subject has (i) at least one (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK1 gene that results in theexpression of a TrkA protein including one or more (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) mutations (e.g., any of the mutations in TrkAdescribed herein) and/or (ii) at least one (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) point mutation in a NTRK2 gene that results in theexpression of a TrkB protein including one or more (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) mutations (e.g., any of the TrkB mutationsdescribed herein), and/or (iii) at least one (e.g., two, three, four,five, six, or seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) point mutation in a NTRK3 gene that results in theexpression of a TrkC protein including one or more (e.g., two, three,four, five, six, or seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) mutations (e.g., any of the mutations in TrkCdescribed herein), comprises performing an assay to determine thepresence of the at least one point mutation in a NTRK1 gene and/or theat least one point mutation in a NTRK2 gene and/or the at least onepoint mutation in a NTRK3 gene in a cancer cell in the sample (e.g., abiopsy sample) from the subject. Any of the assays described herein canbe used to determine the presence of the at least one point mutation ina NTRK1 gene and/or the at least one point mutation in a NTRK2 geneand/or the at least one point mutation in a NTRK3 gene. In addition, anyof the kits provided herein can be used in an assay to determine thepresence of the at least one point mutation in a NTRK1 gene and/or theat least one point mutation in a NTRK2 gene and/or the at least onepoint mutation in a NTRK3 gene. In some examples, the assay includessequencing a segment of a NTRK1 gene including the at least one pointmutation and/or a segment of a NTRK2 gene including the at least onepoint mutation and/or a segment of a NTRK3 gene including the at leastone point mutation.

Methods of Selecting a Subject Having a Cancer for Participation in aClinical Study

Also provided herein are methods of selecting a subject having a cancerfor participation in a clinical study that includes administration oftreatment for a cancer that include (a) determining whether a cancercell in a sample obtained from the subject has (i) at least one (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) point mutation in a NTRK1 gene thatresults in the expression of a TrkA protein including a mutation at oneor more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid position(s)selected from the group consisting of: 517, 542, 568, 573, 589, 595,599, 600, 602, 646, 656, 657, 667, and 676 (e.g., one or more of thesubstitutions of G517R, A542V, V573M, F589L, F589C, G595S, G595R, D596V,F600L, F646V, C656Y, C656F, L657V, G667S, G667C, and Y676S) and/or (ii)at least one (e.g., two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK2 gene that results in the expression of a TrkB protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid positions selected from the group consisting of: 545, 570, 596,601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702 (e.g., one ormore of the substitutions of G545R, A570V, Q596E, Q596P, V601G, F617L,F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S,and G713S), and/or (iii) at least one (e.g., two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, orfifteen) point mutation in a NTRK3 gene that results in the expressionof a TrkC protein including a mutation at one or more (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) amino acid position(s) selected from the groupconsisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685,686, 696, and 705 (e.g., one or more of the substitutions of G545R,A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A); and (b)selecting a subject having a cancer cell having (i) at least one (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) point mutation in a NTRK1 gene thatresults in the expression of a TrkA protein including a mutation at oneor more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid position(s)selected from the group consisting of: 517, 542, 568, 573, 589, 595,599, 600, 602, 646, 656, 657, 667, and 676 (e.g., one or more of thesubstitutions of G517R, A542V, V573M, F589L, F589C, G595S, G595R, D596V,F600L, F646V, C656Y, C656F, L657V, G667S, G667C, and Y676S), and/or (ii)at least one (e.g., two, three, four, five, six, seven, eight, nine,ten, eleven, twelve, thirteen, fourteen, or fifteen) point mutation in aNTRK2 gene that results in the expression of a TrkB protein including amutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid positions selected from the group consisting of: 545, 570, 596,601, 617, 623, 624, 628, 630, 672, 682, 683, 693, and 702 (e.g., one ormore of the substitutions of G545R, A570V, Q596E, Q596P, V601G, F617L,F617C, F617I, G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S,and G713S), and/or (iii) at least one (e.g., two, three, four, five,six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, orfifteen) point mutation in a NTRK3 gene that results in the expressionof a TrkC protein including a mutation at one or more (e.g., two, three,four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,fourteen, or fifteen) amino acid position(s) selected from the groupconsisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685,686, 696, and 705 (e.g., one or more of the substitutions of G545R,A570V, F617L, G623R, D624V, C685Y, C685F, L686V, and G696A), forparticipation in a clinical study that includes administration of atreatment for a cancer.

Also provided herein are methods of selecting a subject having a cancerfor participation in a clinical study that includes administration of aTrk inhibitor that include (a) determining whether a cancer cell in asample obtained from the subject has (i) at least one point (e.g., two,three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) mutation in a NTRK1 gene that results inthe expression of a TrkA protein including a mutation at one or more(e.g., two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, or fifteen) amino acid position(s) selectedfrom the group consisting of: 517, 542, 568, 573, 589, 595, 599, 600,602, 646, 656, 657, 667, and 676 (e.g., one or more of the substitutionsof G517R, A542V, V573M, F589L, F589C, G595S, G595R, D596V, F600L, F646V,C656Y, C656F, L657V, G667S, G667C, and Y676S), and/or (ii) at least one(e.g., two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, or fifteen) point mutation in a NTRK2 genethat results in the expression of a TrkB protein including a mutation atone or more (e.g., two, three, four, five, six, seven, eight, nine, ten,eleven, twelve, thirteen, fourteen, or fifteen) amino acid positionsselected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 672, 682, 683, 693, and 702 (e.g., one or more of thesubstitutions of G545R, A570V, Q596E, Q596P, V601G, F617L, F617C, F617I,G623S, G623R, D624V, R630K, C682Y, C682F, L683V, G693S, and G713S),and/or (iii) at least one (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) pointmutation in a NTRK3 gene that results in the expression of a TrkCprotein including a mutation at one or more (e.g., two, three, four,five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen,or fifteen) amino acid position(s) selected from the group consistingof: 545, 570, 596, 601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and705 (e.g., one or more of the substitutions of G545R, A570V, F617L,G623R, D624V, C685Y, C685F, L686V, and G696A); and (b) selecting asubject having a cancer cell that does not have (i) a point mutation ina NTRK1 gene that results in the expression of a TrkA protein includinga mutation at one or more (e.g., two, three, four, five, six, seven,eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen) aminoacid position(s) selected from the group consisting of: 517, 542, 568,573, 589, 595, 599, 600, 602, 646, 656, 657, 667, and 676 (e.g., one ormore of the substitutions of G517R, A542V, V573M, F589L, F589C, G595S,G595R, D596V, F600L, F646V, C656Y, C656F, L657V, G667S, G667C, andY676S), or (ii) a point mutation in a NTRK2 gene that results in theexpression of a TrkB protein including a mutation at one or more (e.g.,two, three, four, five, six, seven, eight, nine, ten, eleven, twelve,thirteen, fourteen, or fifteen) amino acid positions selected from thegroup consisting of: 545, 570, 596, 601, 617, 623, 624, 628, 630, 672,682, 683, 693, and 702 (e.g., one or more of the substitutions of G545R,A570V, Q596E, Q596P, V601G, F617L, F617C, F617I, G623S, G623R, D624V,R630K, C682Y, C682F, L683V, G693S, and G713S), or (iii) a point mutationin a NTRK3 gene that results in the expression of a TrkC proteinincluding a mutation at one or more (e.g., two, three, four, five, six,seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or fifteen)amino acid position(s) selected from the group consisting of: 545, 570,596, 601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and 705 (e.g.,one or more of the substitutions of G545R, A570V, F617L, G623R, D624V,C685Y, C685F, L686V, and G696A), for participation in a clinical studythat includes administration of a Trk inhibitor.

The cancer can be any of the exemplary cancers described herein. In someembodiments, the subject has previously been identified or diagnosed ashaving a cancer. In some examples, the subject has previously beenadministered a treatment for cancer, and the treatment for cancer hasbeen unsuccessful (e.g., high toxicity in the subject or no positiveresponse to the previously administered treatment for cancer).

In some examples, the step of determining whether a cancer cell in asample obtained from the subject has the at least one point mutation(e.g., any of the point mutations described herein) in a NTRK1 gene thatresults in the expression of a TrkA including a mutation at one or moreamino acid position(s) and/or the at least one point mutation (e.g., anyof the point mutations described herein) in a NTRK2 gene that results inthe expression of a TrkB including a mutation at one or more amino acidposition(s) and/or the at least one point mutation (e.g., any of thepoint mutations described herein) in a NTRK3 gene that results in theexpression of a TrkC including a mutation at one or more amino acidposition(s), comprises performing an assay to determine the presence ofthe at least one point mutation in a NTRK1 gene and/or the at least onepoint mutation in a NTRK2 gene and/or the at least one point mutation ina NTRK3 gene in a cancer cell in a sample (e.g., a biopsy sample) fromthe subject. Any of the assays described herein can be used to determinethe presence of the at least one point mutation in a NTRK1 gene and/orthe at least one point mutation in a NTRK2 gene and/or the at least onepoint mutation in a NTRK3 gene. In addition, any of the kits providedherein can be used in an assay to determine the presence of the at leastone point mutation in a NTRK1 gene and/or the at least one pointmutation in a NTRK2 gene and/or the at least one point mutation in aNTRK3 gene. In some examples, the assay includes sequencing a segment ofa NTRK1 including the at least one point mutation and/or a segment of aNTRK2 including the at least one point mutation and/or a segment of aNTRK3 including the at least one point mutation.

Kits

Also provided herein are kits that include one or more (e.g., two,three, four, five, six, or seven) probes that specifically hybridize toa segment of a NTRK1 gene that comprises one of the point mutationsdescribed herein (e.g., any point mutation that results in an amino acidsubstitution at amino acid position 517, 542, 568, 573, 589, 595, 599,600, 602, 646, 656, 657, 667, and 676 in TrkA); and/or one or more(e.g., two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, or fifteen) probes that specificallyhybridize to a segment of a NTRK2 gene that comprises one of the pointmutations described herein (e.g., any point mutation that results in anamino acid substitution at amino acid position 545, 570, 596, 601, 617,623, 624, 628, 630, 672, 682, 683, 693, 702, or 713; and/or one or more(e.g., two, three, four, five, six, seven, eight, nine, ten, eleven,twelve, thirteen, fourteen, or fifteen) probes that specificallyhybridizes to a segment of a NTRK3 gene that comprises one of the pointmutations described herein (e.g., any point mutation that results in anamino acid substitution at amino acid position 545, 570, 596, 601, 617,623, 624, 628, 630, 675, 685, 686, 696, 705, or 730 in TrkC). Forexample, the kits provided herein can include one or more probes thatspecifically hybridize to a segment of a NTRK1 gene that encodes amutation selected from the group consisting of: G517R, A542V, V573M,F589L, F589C, G595S, G595R, D596V, F600L, F646V, C656Y, C656F, L657V,G667S, G667C, and Y676S in a TrkA protein); and/or one or more probesthat specifically hybridize to a segment of a NTRK2 gene that encodes amutation selected from the group consisting of: G545R, A570V, Q596E,Q596P, V601G, F617L, F617C, F617I, G623S, G623R, D624V, R630K, C682Y,C682F, L683V, G693S, and G713S; and/or one or more probes thatspecifically hybridizes to a segment of a NTRK3 gene that encodes amutation selected from the group consisting of: G545R, A570V, F617L,G623R, D624V, C685Y, C685F, L686V, and G696A.

Each of the one or more probes can have a length of 8, 9, 10, 11, 12,13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,31, 32, 33, 34, or 35 nucleotides. In some embodiments, the one or moreprobes include a detectable label (e.g., a fluorophore, a quencher, aradioisotope, or a metal). In some embodiments, the one or more probescan be covalently attached to a substrate (e.g., a film, a plate, or abead).

The invention is further described in the following examples, which donot limit the scope of the invention described in the claims.

EXAMPLES Example 1. Identification of Trk Inhibitor-Resistance PointMutations

A genetic screen was performed to determine if resistance mutationsarise in cancer subjects having NTRK⁺ tumors treated with Trkinhibitors. In the genetic screen cDNAs harboring the MPRIP-NTRK1oncogene were introduced into Ba/F3 cells. The Ba/F3 cells were treatedwith the mutagen, 100 μg/mL N-ethyl-N-nitrosourea (ENU; Sigma Aldrich,St. Louis, Mo.), overnight. The ENU-treated Ba/F3 cells were plated into96-well plates in media supplemented with different concentrations of(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide sulfate (25nM, 50 nM, 100 nM, 250 nM, 500 nM, or 1 μM). The wells were observed formedia color change and cell growth. The contents of the outgrown wellswere expanded in 12-well plates in media supplemented with(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate at the same concentration as in the initial 96-well plate. Atconfluence, the cells were collected and genomic DNA was extracted. TheNTRK1 kinase region was amplified and the PCR products were purified andsequenced. A plasmids encoding MPRIP-NTRK1 mutations were generated withQuickChange site-directed mutagenesis according to the manufacturer'sinstructions using a sequence encoding a wildtype MPRIP-NTRK1 fusionprotein as a template. Each mutation was confirmed by DNA sequencing.The Ba/F3 cells and NIH353 cells expressing MPRIP-NTRK1 mutants weregenerated by infecting Ba/F3 and NIH353 parental cells with lentivirusencoding the mutation MPRIP-NTRK1 fusion proteins, followed by selectionwith puromycin. A flow chart showing the steps in the experimentalmethods is shown in FIG. 1.

The identified(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate resistance point mutations resulted in the following amino acidsubstitutions in TrkA: V573M, F589L, F600L, G667S, and Y676S. Thelocation of three substitutions in TrkA resulting from(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate resistance point mutations were mapped onto the crystalstructure of TrkA: V573, F589, and G667 (FIG. 2) and a diagram of thedomain structure of TrkA (FIG. 3). Cancer cells having a MPRIP-NTRK1point mutation have increased resistance to(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (FIG. 4).

These experiments show that the presence of one or more of the V573M,F589L, F600L, G667S, and Y676S substitutions in TrkA (or one or more ofthe corresponding point mutations in a NTRK1 gene) in a cancer cell canbe used to predict the resistance of the cancer cell to(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate and other Trk inhibitors, and indicate that the cancer cell willnot be sensitive to treatment with(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate and other Trk inhibitors.

Example 2. Identification of Trk Inhibitor-Resistance Point Mutations

N-ethyl-N-nitrosourea (ENU)-exposed Ba/F3-MPRIP-NTRK1 andBa/F3-TRIM24-NTRK2 cells were used to generate mutations permittinggrowth of Ba/F3 cells in the absence of IL-3 despite the presence of100, 250, or 500 nM(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate. The Mutations identified by genomic DNA sequencing in theinitial screen were validated by cloning the mutation-bearing cDNAs backinto Ba/F3 cells to evaluate their sensitivity to(S)—N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDESULFATE using both proliferation assays and TRK phosphorylation byimmunoblot analyses. Modeling of the mutations was performed by mappingof the amino acid substitutions onto a drug-bound TRK kinase domaincrystal structure.

Mutations at 6 amino acid positions in the TRKA protein and 3 amino acidpositions in the TRKB protein that induce resistance to(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate were identified. In the TRKA kinase domain, the(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate resistance mutations of V573M, and F589L/C, G595S, F600L, F646V,and G667S were identified. In the TRKB kinase domain, the(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate resistance mutations of Q596E/P, F617L/C/I, and G623S wereidentified. These TRK mutations reduce target inhibition by(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate as measured by TRK tyrosine phosphorylation and resultantdownstream signaling through the MAPK or other critical pathways.

Example 3. Identification of TRKA and TRKB Kinase Domain Mutations thatInduce Resistance to a Pan-TRK Inhibitor

A mutagenesis and genetic screening approach to identify candidatemutations in TRKA and TRKB that mediate resistance to(S)—N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDESULFATE was performed. A flow chart showing the steps in theexperimental methods is shown in FIG. 5.

Ba/F3 cells stably expressing MPRIP-NTRK1 or TRIM24-NTRK2 were treatedovernight with 100 mg/ml N-Ethyl-N-nitrosourea (ENU), pelleted,resuspended in fresh media, and distributed in 96-well plates in 200 μLmedia supplemented with(S)—N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDESULFATE (100, 250, and 500 nM). The wells were observed for media colorchange and cell growth. The contents of outgrown wells were expanded in12-well plates in media supplemented with(S)—N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDESULFATE at the same concentration as in the initial 96-well plate. Atconfluence, cells were collected and genomic DNA was extracted. TheNTRK1 and NTRK2 kinase region was PCR-amplified and sequenced. Plasmidsencoding MPRIP-NTRK1 and TRIM24-NTRK2 mutations were generated withQuickChange site-directed mutagenesis and confirmed by DNA sequencing.Ba/F3 cells and NIH3T3 cells expressing MPRIP-NTRK1 mutants weregenerated by infecting Ba/F3 and NIH3T3 parental cells with lentivirusencoding MPRIP-NTRK1 mutation followed by selection with puromycin.

The identified(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate resistance point mutations resulted in the following amino acidsubstitutions in RIP-TrkA: V573M, F589L, F589C, G595R, F600L, F646V,G667S, and Y676S (FIG. 6A). The location of selected substitutions inTrkA resulting from(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate resistance point mutations were mapped onto a diagram of thedomain structure of TrkA (FIG. 6B) and the crystal structure of TrkA(FIG. 6C). Cancer cells having a MPRIP-NTRK1 point mutation resulting inamino acid substitutions V573M, F589L, and G667S exhibit increasedresistance to(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (FIG. 7). TRKA and downstream signaling is not inhibited inNIH3T3 cells expressing these TRKA kinase domain mutations: TRKA, andERK1/2 activation are sensitive to(S)—N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDESULFATE inhibition in NIH3T3 cells expressing MPRIP-NTRK1 wr¹ fusion,whereas NIH3T3 cells expressing MPRIP-NTRK 1 [V^(73M)],MPRIP-NTRK1^([F589L]) or MPRIP-NTRK1^([G667S]) fusions are resistant(FIG. 8).

The identified(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate resistance point mutations resulted in the following amino acidsubstitutions in TRIM24-TrkB: Q596E, Q596P, V601G, F617C, F617I, F617I,G623S, R630K, and G713S (FIG. 9A). The location of selectedsubstitutions in TrkB resulting from(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate resistance point mutations were mapped onto a diagram of thedomain structure of TrkB (FIG. 9B) and the crystal structure of TrkB(FIG. 9C). Cancer cells having a TRIM24-NTRK2 point mutation resultingin amino acid substitutions V601G, G623S, and R630K exhibit increasedresistance to(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate (FIG. 10). TRKB and downstream signaling is not inhibited inNIH3T3 cells expressing these TRKB kinase domain mutations: TRKB, andERK1/2 activation are sensitive to(S)—N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE SULFATEinhibition in NIH3T3 cells expressing TRIM24-NTRK2^([WT]) fusion,whereas NIH3T3 cells expressing TRIM24-NTRK2^([V601G]),TRIM24-NTRK2^([G623S]) or TRIM24-NTRK2^([R630K]) fusions are resistant.(FIG. 11).

FIG. 12 shows the IC₅₀ of certain Ba/F3(S)—N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDESULFATE-resistant clones that were identified. The IC₅₀ measurements forthe mutations shown were determined by an average of 3 experiments.Clones are ordered by conserved amino acids residues between TRKA andTRKB.

An alignment of kinase domains from selected oncogenes with knownresistance mutations is shown in FIG. 13.

Novel mutations in the TRKA kinase domain of the MPRIP-NTRK1 oncogeneand in the TRKB kinase domain of TRIM24-NTRK2 were identified using acombined mutagenesis/genetic screen. All mutations identified conferresistance to the pan-TRK inhibitor(S)—N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDE SULFATE asassessed by cellular proliferation assays and measurement of cellsignaling. The majority of the mutations cluster to the back of theATP/drug-binding pocket, possibly functioning by altering the topologyof this pocket, thereby inhibiting(S)—N-(5-((R)-2-(2,5-DIFLUOROPHENYL)PYRROLIDIN-1-YL)PYRAZOLO[1,5-A]PYRIMIDIN-3-YL)-3-HYDROXYPYRROLIDINE-1-CARBOXAMIDESULFATE binding. Evaluation of tumors or circulating free DNA at diseaseprogression for these and other resistance mutations permits the use ofstructurally distinct TRK inhibitors to overcome drug resistance.

Example 4. Trk Enzyme Assay

The activity of the various Trk compounds exemplified in Table 6 wasdetermined by monitoring the incorporation of [³³P]PO₄ from [γ-³³P]ATPinto poly-EAY (Sigma-Aldrich, P3899).

TABLE 6 Compounds tested in the Trk Enzyme Assay Compound No. CompoundStructure Compound Name 1

(R)-N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3- hydroxyazetidine-1-carboxamide 2

(R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1,1- dimethylurea 3

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)urea 4

(R)-1-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3- methylurea 5

(R)-N-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3- hydroxyazetidine-1-carboxamide 6

(R)-3-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-1-(2- hydroxyethyl)-1-methylurea 7

(R)-N-(6-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)imidazo[1,2-b]pyridazin-3-yl)-3-hydroxy-3-methylazetidine-1-carboxamide 8

(R)-3-(5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-1,1- dimethylurea 9

(R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxyazetidine-1-carboxamide 10

(R)-N-(5-(2-(2-chloro-5-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxy-3-methylazetidine-1- carboxamide 11

(R)-N-(5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3- hydroxyazetidine-1-carboxamide 12

(R)-5-(2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3- carboxamide 13

(R)-N-cyclopropyl-5-(2-(5-fluoro- pyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide 14

(R)-5-(2-(5-fluoro-2-methoxypyridin- 3-yl)pyrrolidin-1-yl)-N-methoxy-pyrazolo[1,5-a]pyrimidine-3- carboxamide 15

(R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)-N-(1-methylcyclopropyl)pyrazolo [1,5-a]pyrimidine-3-carboxamide 16

(6R)-9-fluoro-13-oxa-2,11,17,21,22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]-hexacosa-1(25),7,9,11,19(26),20,23- heptaen-18-one 17

(6R,15R)-9-fluoro-15-hydroxy-13-oxa- 2,11,17,21,22,25-hexaazapentacyclo-[17.5.2.0^(2,6).0^(7,12).0^(22,26)]-hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one 18

(6R)-9-fluoro-13-oxa-2,11,18,22,23,26-hexaazapentacyclo[18.5.2.0^(2,6).0^(7,12).0^(23,27)]-heptacosa-1(26),7,9,11,20(27),21,24- heptaen-19-one 19

(6R)-9-fluoro-13-oxa-2,17,21,22,25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23- heptaen-18-one 20

(6R)-12-oxa-2,16,20,21,24,26-hexaazapentacyclo[16.5.2.^(17,11).0^(2,6).0^(21,25)]-hexacosa-1(24),7(26),8,10,18(25),19,22- heptaen-17-one 21

1-[(6R)-9-fluoro-13-oxa-2,16,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22- heptaen-16-yl]ethan-1-one 22

(6R)-9-fluoro-13,16-dioxa-2,11,20,21,24-pentaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]-pentacosa-1(24),7,9,11,18(25),19,22- heptaen-17-one 23

(6R)-9,15,15-trifluoro-13-oxa-2,11,17,21, 22,25-hexaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen-18-one 24

(6R,13S)-9-fluoro-13-methyl-2,11,15, 19,20,23-hexaazapentacyclo[15.5.2.^(17,11).0^(2,6).0^(20,24)]pentacosa-1(23),7,9,17(24),18,21-hexaene- 16,25-dione 25

(6R)-9-fluoro-15,15-dimethyl-13-oxa- 2,11,17,21,22,25-hexaazapentacyclo[17,5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7,9,11,19(26),20,23-heptaen- 18-one 26

(15S)-4,4,9-trifluoro-15-hydroxy-13-oxa-2,17,21,22.25-pentaazapentacyclo[17.5.2.0^(2,6).0^(7,12).0^(22,26)]hexacosa-1(25),7(12),8,10,19(26),20,23-heptaen- 18-one 27

(6R,15S)-9-fluoro-15-methyl-2,11,16, 20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen- 17-one 28

(6R,15R)-9-fluoro-15-methyl-2,11,16,20, 21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17- one

The assays were conducted in 96-well polypropylene v-bottom microtitreplates (Corning, Costar® 3363) in a total volume of 50 μL. Reactionmixtures typically contained 25 mM Na⁺MOPS, pH 7.4, 5 mM MgCl₂, 0.005%Triton X-100, 2% DMSO, 1 mM DTT, 5 M [³³P]ATP (50 μCi/mL), 100 jag/mLpoly-EAY, Trk enzyme (Trk A, B or C, wild-type or mutant at anappropriate concentration ranging from 0.1-10 nM, depending on thecompound) and compound varying over a 10-point, three-fold dilutionseries ranging from 2000 to 0.1 nM. Incubations were conducted at 22° C.for 60 minutes and quenched by the addition of 100 μL aliquots of 25%trichloroacetic acid. The radiolabeled product was then captured onglass fiber filter plates (PerkinElmer, Unifilter®-96, GF/B®) and washedwith 5% phosphoric acid to remove unbound radiolabel using a Tomtec MACHIII Harvester 96®. After adding 35 μL/well of Bio-Safe II™ liquidscintillation cocktail (Research Products International), the plateswere counted in a TopCount NXT (PerkinElmer) using a counting time of 30s/well. The activity at each concentration of compound was expressed aspercent of control (POC) and plotted versus compound concentration. AnIC₅₀ was estimated using a 4-parameter logistic model fit to thedose-response plots, with IC₅₀ being defined as the concentration ofcompound where the best-fit curve crosses 50 POC. The IC₅₀ values forthe compounds tested in this assay are provided in Table 7.

TABLE 7 IC₅₀ values of compounds tested in the assay of Example 4. IC₅₀(nM) Compound TrkA TrkA TrkA TrkA TrkA TrkB TrkC TrkC Number TrkA WTV573M F589L G595R G667C G667S TrkB WT G623R TrkC WT G623R F617L 1 1.094.9 124.0 24.8 91.3 30.1 5.7 59.7 <2.5 29.3 58.0 2 0.8 76.4 61.5 19.446.3 21.3 4.5 34.1 <2.5 23.1 37.6 3 2.8 627.6 577.5 61.0 295.7 91.1 11.990.0 4.5 55.7 273.0 3 2.5 547.4 384.8 57.0 298.1 108.5 10.6 132.3 3.170.8 177.0 5 1.1 151.6 231.6 84.6 141.2 38.5 5.9 131.9 <2.5 95.0 153.7 60.8 74.9 78.5 25.3 55.1 23.3 5.0 27.5 <2.5 24.1 49.7 7 <0.5 67.1 83.130.5 52.5 26.4 7.0 47.9 <2.5 22.7 42.5 8 0.9 129.3 153.5 49.6 84.2 19.75.0 64.6 <2.5 54.9 67.1 9 0.8 106.4 90.7 91.9 76.5 21.6 4.6 104.3 <2.592.6 66.5 10 0.9 104.8 102.6 107.3 89.2 27.0 6.5 149.8 <2.5 100.5 80.111 6.9 1198.9 1084.1 560.6 830.4 274.6 19.0 671.4 4.4 445.7 476.2 12<0.5 14.9 21.0 1.0 15.6 3.6 3.3 1.3 <2.5 1.6 9.9 13 <0.5 20.9 37.2 3.332.4 4.1 3.5 2.7 <2.5 3.1 8.7 14 <0.5 12.1 14.8 1.5 9.0 2.8 4.4 1.5 <2.52.7 12.4 15 <0.5 6.3 7.3 1.6 8.1 1.4 <2.5 1.6 <2.5 1.7 <5.0 16 <0.5 <5.0<1.0 0.9 1.1 0.4 2.9 0.9 <2.5 1.3 <5.0 17 <0.5 <5.0 2.1 1.5 2.6 0.7 3.61.1 <2.5 1.8 <5.0 18 <0.5 <5.0 3.9 1.3 2.6 0.6 4.1 1.0 <2.5 1.4 5.5 190.5 <5.0 1.1 1.2 0.9 0.3 4.4 1.0 <2.5 1.8 5.1 20 <0.5 36.5 48.3 2.7 13.33.2 3.1 3.1 <2.5 3.1 18.3 21 0.6 29.1 66.3 7.3 22.2 8.4 5.6 12.4 <2.57.8 48.5 22 0.5 <5.0 8.4 1.5 5.7 0.9 2.9 1.3 <2.5 1.5 5.4 23 0.7 <5.0<1.0 1.6 0.8 0.3 6.1 1.1 2.7 2.1 5.8 24 0.5 38.3 86.8 3.3 22.3 4.7 4.74.2 <2.5 4.5 61.9 25 1.0 <5.0 1.1 3.0 1.0 0.5 8.7 2.3 4.0 4.7 8.1 26 0.6<5.0 3.9 2.1 1.0 0.5 3.3 1.8 <2.5 2.6 9.6 27 <0.5 9.3 21.0 1.5 5.6 2.13.4 1.7 <2.5 2.2 9.5 28 0.5 <5.0 3.3 2.0 9.8 2.3 3.2 1.9 <2.5 2.8 <5.0

Other Embodiments

It is to be understood that while the invention has been described inconjunction with the detailed description thereof, the foregoingdescription is intended to illustrate and not limit the scope of theinvention, which is defined by the scope of the appended claims. Otheraspects, advantages, and modifications are within the scope of thefollowing claims.

What is claimed is:
 1. A method of treating a subject having aTrk-associated cancer, the method comprising: (a) administering one ormore doses of a first Trk inhibitor to the subject for a period of time,wherein the first Trk inhibitor is(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate; and (b) after (a), administering a treatment comprising one ormore doses of the first Trk inhibitor and a second Trk inhibitor to thesubject, wherein the second Trk inhibitor is (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;wherein the subject is identified as having at least one solvent frontmutation, wherein the at least one solvent front mutation comprises (i)at least one point mutation in a NTRK1 gene that results in theexpression of a TrkA kinase polypeptide comprising a mutation at aminoacid position 595, and/or (ii) at least one point mutation in a NTRK3gene that results in the expression of a TrkC kinase polypeptidecomprising a mutation at amino acid position 623, wherein the at leastone solvent front mutation is expressed in the Trk-associated cancer. 2.The method of claim 1, wherein the at least one solvent front mutationcomprises TrkA G595R, TrkC G623R, or both.
 3. The method of claim 1,wherein the subject, following administration of one or more doses ofthe first Trk inhibitor in step (a), is identified as having at leastone solvent front mutation, wherein the at least one solvent frontmutation comprises (i) at least one point mutation in a NTRK1 gene thatresults in the expression of a TrkA kinase polypeptide comprising amutation at amino acid position 595, and/or (ii) at least one pointmutation in a NTRK3 gene that results in the expression of a TrkC kinasepolypeptide comprising a mutation at amino acid position 623, whereinthe at least one solvent front mutation is expressed in theTrk-associated cancer.
 4. The method of claim 3, wherein the at leastone solvent front mutation comprises TrkA G595R, TrkC G623R, or both. 5.The method of claim 1, wherein the Trk-associated cancer is selectedfrom the group consisting of: adenocarcinoma, adrenal gland corticalcarcinoma, adrenal gland neuroblastoma, anus squamous cell carcinoma,appendix adenocarcinoma, bladder urothelial carcinoma, bile ductadenocarcinoma, bladder carcinoma, bladder urothelial carcinoma, bonechordoma, bone marrow leukemia lymphocytic chronic, bone marrow leukemianon-lymphocytic acute myelocytic, bone marrow lymph proliferativedisease, bone marrow multiple myeloma, bone sarcoma, brain astrocytoma,brain glioblastoma, brain medulloblastoma, brain meningioma, brainoligodendroglioma, breast adenoid cystic carcinoma, breast carcinoma,breast ductal carcinoma in situ, breast invasive ductal carcinoma,breast invasive lobular carcinoma, breast metaplastic carcinoma, cervixneuroendocrine carcinoma, cervix squamous cell carcinoma, colonadenocarcinoma, colon carcinoid tumor, duodenum adenocarcinoma,endometrioid tumor, esophagus adenocarcinoma, eye intraocular melanoma,eye intraocular squamous cell carcinoma, eye lacrimal duct carcinoma,fallopian tube serous carcinoma, gallbladder adenocarcinoma, gallbladderglomus tumor, gastroesophageal junction adenocarcinoma, head and neckadenoid cystic carcinoma, head and neck carcinoma, head and neckneuroblastoma, head and neck squamous cell carcinoma, kidney chromophorecarcinoma, kidney medullary carcinoma, kidney renal cell carcinoma,kidney renal papillary carcinoma, kidney sarcomatoid carcinoma, kidneyurothelial carcinoma, leukemia lymphocytic, liver cholangiocarcinoma,liver hepatocellular carcinoma, lung adenocarcinoma, lung adenosquamouscarcinoma, lung atypical carcinoid, lung carcinosarcoma, lung large cellneuroendocrine carcinoma, lung non-small cell lung carcinoma, lungsarcoma, lung sarcomatoid carcinoma, lung small cell carcinoma, lungsmall cell undifferentiated carcinoma, lung squamous cell carcinoma,lymph node lymphoma diffuse large B cell, lymph node lymphoma follicularlymphoma, lymph node lymphoma mediastinal B-cell, lymph node lymphomaplasmablastic lung adenocarcinoma, lymphoma follicular lymphoma,non-Hodgkin's lymphoma, nasopharynx and paranasal sinusesundifferentiated carcinoma, ovary carcinoma, ovary carcinosarcoma, ovaryclear cell carcinoma, ovary epithelial carcinoma, ovary granulosa celltumor, ovary serous carcinoma, pancreas carcinoma, pancreas ductaladenocarcinoma, pancreas neuroendocrine carcinoma, peritoneummesothelioma, peritoneum serous carcinoma, placenta choriocarcinoma,pleura mesothelioma, prostate acinar adenocarcinoma, prostate carcinoma,rectum adenocarcinoma, rectum squamous cell carcinoma, skin adnexalcarcinoma, skin basal cell carcinoma, skin melanoma, skin Merkel cellcarcinoma, skin squamous cell carcinoma, small intestine adenocarcinoma,small intestine gastrointestinal stromal tumors (GISTs), soft tissueangiosarcoma, soft tissue Ewing sarcoma, soft tissuehemangioendothelioma, soft tissue inflammatory myofibroblastic tumor,soft tissue leiomyosarcoma, soft tissue liposarcoma, soft tissueneuroblastoma, soft tissue paraganglioma, soft tissue perivascularepitheliod cell tumor, soft tissue sarcoma, soft tissue synovialsarcoma, stomach adenocarcinoma, stomach adenocarcinoma diffuse-type,stomach adenocarcinoma intestinal type, stomach adenocarcinomaintestinal type, stomach leiomyosarcoma, thymus carcinoma, thymusthymoma lymphocytic, thyroid papillary carcinoma, unknown primaryadenocarcinoma, unknown primary carcinoma, unknown primary malignantneoplasm, unknown primary melanoma, unknown primary sarcomatoidcarcinoma, unknown primary squamous cell carcinoma, unknownundifferentiated neuroendocrine carcinoma, unknown primaryundifferentiated small cell carcinoma, uterus carcinosarcoma, uterusendometrial adenocarcinoma, uterus endometrial adenocarcinomaendometrioid, uterus endometrial adenocarcinoma papillary serous, anduterus leiomyosarcoma.
 6. A method of treating a subject having aTrk-associated cancer, the method comprising administering to thesubject one or more doses of(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate and (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25), 19,22-heptaen-17-one; wherein the subject isidentified as having at least one solvent front mutation, wherein the atleast one solvent front mutation comprises (i) at least one pointmutation in a NTRK1 gene that results in the expression of a TrkA kinasepolypeptide comprising a mutation at amino acid position 595, and/or(ii) at least one point mutation in a NTRK3 gene that results in theexpression of a TrkC kinase polypeptide comprising a mutation at aminoacid position 623, wherein the at least one solvent front mutation isexpressed in the Trk-associated cancer.
 7. The method of claim 6,wherein the at least one solvent front mutation comprises TrkA G595R,TrkC G623R, or both.
 8. The method of claim 6, wherein the subject waspreviously administered one or more doses of(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate prior to being identified as having at least one solvent frontmutation, wherein the at least one solvent front mutation comprises (i)at least one point mutation in a NTRK1 gene that results in theexpression of a TrkA kinase polypeptide comprising a mutation at aminoacid position 595, and/or (ii) at least one point mutation in a NTRK3gene that results in the expression of a TrkC kinase polypeptidecomprising a mutation at amino acid position 623, wherein the at leastone solvent front mutation is expressed in the Trk-associated cancer. 9.The method of claim 8, wherein the at least one solvent front mutationcomprises TrkA G595R, TrkC G623R, or both.
 10. The method of claim 6,wherein the Trk-associated cancer is selected from the group consistingof: adenocarcinoma, adrenal gland cortical carcinoma, adrenal glandneuroblastoma, anus squamous cell carcinoma, appendix adenocarcinoma,bladder urothelial carcinoma, bile duct adenocarcinoma, bladdercarcinoma, bladder urothelial carcinoma, bone chordoma, bone marrowleukemia lymphocytic chronic, bone marrow leukemia non-lymphocytic acutemyelocytic, bone marrow lymph proliferative disease, bone marrowmultiple myeloma, bone sarcoma, brain astrocytoma, brain glioblastoma,brain medulloblastoma, brain meningioma, brain oligodendroglioma, breastadenoid cystic carcinoma, breast carcinoma, breast ductal carcinoma insitu, breast invasive ductal carcinoma, breast invasive lobularcarcinoma, breast metaplastic carcinoma, cervix neuroendocrinecarcinoma, cervix squamous cell carcinoma, colon adenocarcinoma, coloncarcinoid tumor, duodenum adenocarcinoma, endometrioid tumor, esophagusadenocarcinoma, eye intraocular melanoma, eye intraocular squamous cellcarcinoma, eye lacrimal duct carcinoma, fallopian tube serous carcinoma,gallbladder adenocarcinoma, gallbladder glomus tumor, gastroesophagealjunction adenocarcinoma, head and neck adenoid cystic carcinoma, headand neck carcinoma, head and neck neuroblastoma, head and neck squamouscell carcinoma, kidney chromophore carcinoma, kidney medullarycarcinoma, kidney renal cell carcinoma, kidney renal papillarycarcinoma, kidney sarcomatoid carcinoma, kidney urothelial carcinoma,leukemia lymphocytic, liver cholangiocarcinoma, liver hepatocellularcarcinoma, lung adenocarcinoma, lung adenosquamous carcinoma, lungatypical carcinoid, lung carcinosarcoma, lung large cell neuroendocrinecarcinoma, lung non-small cell lung carcinoma, lung sarcoma, lungsarcomatoid carcinoma, lung small cell carcinoma, lung small cellundifferentiated carcinoma, lung squamous cell carcinoma, lymph nodelymphoma diffuse large B cell, lymph node lymphoma follicular lymphoma,lymph node lymphoma mediastinal B-cell, lymph node lymphomaplasmablastic lung adenocarcinoma, lymphoma follicular lymphoma,non-Hodgkin's lymphoma, nasopharynx and paranasal sinusesundifferentiated carcinoma, ovary carcinoma, ovary carcinosarcoma, ovaryclear cell carcinoma, ovary epithelial carcinoma, ovary granulosa celltumor, ovary serous carcinoma, pancreas carcinoma, pancreas ductaladenocarcinoma, pancreas neuroendocrine carcinoma, peritoneummesothelioma, peritoneum serous carcinoma, placenta choriocarcinoma,pleura mesothelioma, prostate acinar adenocarcinoma, prostate carcinoma,rectum adenocarcinoma, rectum squamous cell carcinoma, skin adnexalcarcinoma, skin basal cell carcinoma, skin melanoma, skin Merkel cellcarcinoma, skin squamous cell carcinoma, small intestine adenocarcinoma,small intestine gastrointestinal stromal tumors (GISTs), soft tissueangiosarcoma, soft tissue Ewing sarcoma, soft tissuehemangioendothelioma, soft tissue inflammatory myofibroblastic tumor,soft tissue leiomyosarcoma, soft tissue liposarcoma, soft tissueneuroblastoma, soft tissue paraganglioma, soft tissue perivascularepitheliod cell tumor, soft tissue sarcoma, soft tissue synovialsarcoma, stomach adenocarcinoma, stomach adenocarcinoma diffuse-type,stomach adenocarcinoma intestinal type, stomach adenocarcinomaintestinal type, stomach leiomyosarcoma, thymus carcinoma, thymusthymoma lymphocytic, thyroid papillary carcinoma, unknown primaryadenocarcinoma, unknown primary carcinoma, unknown primary malignantneoplasm, unknown primary melanoma, unknown primary sarcomatoidcarcinoma, unknown primary squamous cell carcinoma, unknownundifferentiated neuroendocrine carcinoma, unknown primaryundifferentiated small cell carcinoma, uterus carcinosarcoma, uterusendometrial adenocarcinoma, uterus endometrial adenocarcinomaendometrioid, uterus endometrial adenocarcinoma papillary serous, anduterus leiomyosarcoma.
 11. A method of treating a subject having aTrk-associated cancer, the method comprising: (a) administering one ormore doses of a first Trk inhibitor to the subject for a period of time,wherein the first Trk inhibitor is(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate; and (b) after (a), administering a treatment comprising one ormore doses of the first Trk inhibitor and a second Trk inhibitor to thesubject, wherein the second Trk inhibitor is (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25),19,22-heptaen-17-one;wherein the subject is identified as having (i) at least one pointmutation in a NTRK1 gene that results in the expression of a TrkA kinasepolypeptide comprising a mutation at one or more amino acid position(s)selected from the group consisting of: 517, 542, 568, 573, 589, 595,599, 600, 602, 646, 656, 657, 667, and 676, and/or (ii) at least onepoint mutation in a NTRK2 gene that results in the expression of a TrkBkinase polypeptide comprising a mutation at one or more amino acidposition(s) selected from the group consisting of: 545, 570, 596, 601,617, 623, 624, 628, 630, 672, 682, 683, 693, and 702, and/or (iii) atleast one point mutation in a NTRK3 gene that results in the expressionof a TrkC kinase polypeptide comprising a mutation at one or more aminoacid position(s) selected from the group consisting of: 545, 570, 596,601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and
 705. 12. Themethod of claim 11, wherein the at least one point mutation comprises(i) at least one point mutation in a NTRK1 gene that results in theexpression of a TrkA kinase polypeptide comprising a mutation selectedfrom the group consisting of: G517R, A542V, Q568x, V573M, F589L, F589C,G595S, G595R, F600L, R602x, F646V, C656Y, C656F, L657V, G667C, G667S,and Y676S, and/or (ii) at least one point mutation in a NTRK2 gene thatresults in the expression of a TrkB kinase polypeptide comprising amutation selected from the group consisting of: G545R, A570V, Q596E,Q596P, V601G, F617L, F617C, F617I, G623S, G623R, D624V, F628x, R630K,F672x, C682Y, C682F, L683V, G693S, and Y702x, and/or (iii) at least onepoint mutation in a NTRK3 gene that results in the expression of a TrkCkinase polypeptide comprising a mutation at one or more amino acidposition(s) selected from the group consisting of: G545R, A570V, Q596x,F617L, G623R, D624V, F628x, R630x, F675x, C685Y, C685F, L686V, G696A,and Y705x.
 13. The method of claim 11, wherein the subject, followingadministration of one or more doses of the first Trk inhibitor in step(a), is identified as having (i) at least one point mutation in a NTRK1gene that results in the expression of a TrkA kinase polypeptidecomprising a mutation at one or more amino acid position(s) selectedfrom the group consisting of: 517, 542, 568, 573, 589, 595, 599, 600,602, 646, 656, 657, 667, and 676, and/or (ii) at least one pointmutation in a NTRK2 gene that results in the expression of a TrkB kinasepolypeptide comprising a mutation at one or more amino acid position(s)selected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 672, 682, 683, 693, and 702, and/or (iii) at least onepoint mutation in a NTRK3 gene that results in the expression of a TrkCkinase polypeptide comprising a mutation at one or more amino acidposition(s) selected from the group consisting of: 545, 570, 596, 601,617, 623, 624, 628, 630, 675, 685, 686, 696, and
 705. 14. The method ofclaim 13, wherein the at least one point mutation comprises (i) at leastone point mutation in a NTRK1 gene that results in the expression of aTrkA kinase polypeptide comprising a mutation selected from the groupconsisting of: G517R, A542V, Q568x, V573M, F589L, F589C, G595S, G595R,F600L, R602x, F646V, C656Y, C656F, L657V, G667C, G667S, and Y676S,and/or (ii) at least one point mutation in a NTRK2 gene that results inthe expression of a TrkB kinase polypeptide comprising a mutationselected from the group consisting of: G545R, A570V, Q596E, Q596P,V601G, F617L, F617C, F617I, G623S, G623R, D624V, F628x, R630K, F672x,C682Y, C682F, L683V, G693S, and Y702x, and/or (iii) at least one pointmutation in a NTRK3 gene that results in the expression of a TrkC kinasepolypeptide comprising a mutation at one or more amino acid position(s)selected from the group consisting of: G545R, A570V, Q596x, F617L,G623R, D624V, F628x, R630x, F675x, C685Y, C685F, L686V, G696A, andY705x.
 15. The method of claim 11, wherein the Trk-associated cancer isselected from the group consisting of: adenocarcinoma, adrenal glandcortical carcinoma, adrenal gland neuroblastoma, anus squamous cellcarcinoma, appendix adenocarcinoma, bladder urothelial carcinoma, bileduct adenocarcinoma, bladder carcinoma, bladder urothelial carcinoma,bone chordoma, bone marrow leukemia lymphocytic chronic, bone marrowleukemia non-lymphocytic acute myelocytic, bone marrow lymphproliferative disease, bone marrow multiple myeloma, bone sarcoma, brainastrocytoma, brain glioblastoma, brain medulloblastoma, brainmeningioma, brain oligodendroglioma, breast adenoid cystic carcinoma,breast carcinoma, breast ductal carcinoma in situ, breast invasiveductal carcinoma, breast invasive lobular carcinoma, breast metaplasticcarcinoma, cervix neuroendocrine carcinoma, cervix squamous cellcarcinoma, colon adenocarcinoma, colon carcinoid tumor, duodenumadenocarcinoma, endometrioid tumor, esophagus adenocarcinoma, eyeintraocular melanoma, eye intraocular squamous cell carcinoma, eyelacrimal duct carcinoma, fallopian tube serous carcinoma, gallbladderadenocarcinoma, gallbladder glomus tumor, gastroesophageal junctionadenocarcinoma, head and neck adenoid cystic carcinoma, head and neckcarcinoma, head and neck neuroblastoma, head and neck squamous cellcarcinoma, kidney chromophore carcinoma, kidney medullary carcinoma,kidney renal cell carcinoma, kidney renal papillary carcinoma, kidneysarcomatoid carcinoma, kidney urothelial carcinoma, leukemialymphocytic, liver cholangiocarcinoma, liver hepatocellular carcinoma,lung adenocarcinoma, lung adenosquamous carcinoma, lung atypicalcarcinoid, lung carcinosarcoma, lung large cell neuroendocrinecarcinoma, lung non-small cell lung carcinoma, lung sarcoma, lungsarcomatoid carcinoma, lung small cell carcinoma, lung small cellundifferentiated carcinoma, lung squamous cell carcinoma, lymph nodelymphoma diffuse large B cell, lymph node lymphoma follicular lymphoma,lymph node lymphoma mediastinal B-cell, lymph node lymphomaplasmablastic lung adenocarcinoma, lymphoma follicular lymphoma,non-Hodgkin's lymphoma, nasopharynx and paranasal sinusesundifferentiated carcinoma, ovary carcinoma, ovary carcinosarcoma, ovaryclear cell carcinoma, ovary epithelial carcinoma, ovary granulosa celltumor, ovary serous carcinoma, pancreas carcinoma, pancreas ductaladenocarcinoma, pancreas neuroendocrine carcinoma, peritoneummesothelioma, peritoneum serous carcinoma, placenta choriocarcinoma,pleura mesothelioma, prostate acinar adenocarcinoma, prostate carcinoma,rectum adenocarcinoma, rectum squamous cell carcinoma, skin adnexalcarcinoma, skin basal cell carcinoma, skin melanoma, skin Merkel cellcarcinoma, skin squamous cell carcinoma, small intestine adenocarcinoma,small intestine gastrointestinal stromal tumors (GISTs), soft tissueangiosarcoma, soft tissue Ewing sarcoma, soft tissuehemangioendothelioma, soft tissue inflammatory myofibroblastic tumor,soft tissue leiomyosarcoma, soft tissue liposarcoma, soft tissueneuroblastoma, soft tissue paraganglioma, soft tissue perivascularepitheliod cell tumor, soft tissue sarcoma, soft tissue synovialsarcoma, stomach adenocarcinoma, stomach adenocarcinoma diffuse-type,stomach adenocarcinoma intestinal type, stomach adenocarcinomaintestinal type, stomach leiomyosarcoma, thymus carcinoma, thymusthymoma lymphocytic, thyroid papillary carcinoma, unknown primaryadenocarcinoma, unknown primary carcinoma, unknown primary malignantneoplasm, unknown primary melanoma, unknown primary sarcomatoidcarcinoma, unknown primary squamous cell carcinoma, unknownundifferentiated neuroendocrine carcinoma, unknown primaryundifferentiated small cell carcinoma, uterus carcinosarcoma, uterusendometrial adenocarcinoma, uterus endometrial adenocarcinomaendometrioid, uterus endometrial adenocarcinoma papillary serous, anduterus leiomyosarcoma.
 16. A method of treating a subject having aTrk-associated cancer, the method comprising administering to thesubject one or more doses of(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate and (6R,15R)-9-fluoro-15-methyl-2,11,16,20,21,24-hexaazapentacyclo[16.5.2.0^(2,6).0^(7,12).0^(21,25)]pentacosa-1(24),7,9,11,18(25), 19,22-heptaen-17-one; wherein the subject isidentified as having (i) at least one point mutation in a NTRK1 genethat results in the expression of a TrkA kinase polypeptide comprising amutation at one or more amino acid position(s) selected from the groupconsisting of: 517, 542, 568, 573, 589, 595, 599, 600, 602, 646, 656,657, 667, and 676, and/or (ii) at least one point mutation in a NTRK2gene that results in the expression of a TrkB kinase polypeptidecomprising a mutation at one or more amino acid position(s) selectedfrom the group consisting of: 545, 570, 596, 601, 617, 623, 624, 628,630, 672, 682, 683, 693, and 702, and/or (iii) at least one pointmutation in a NTRK3 gene that results in the expression of a TrkC kinasepolypeptide comprising a mutation at one or more amino acid position(s)selected from the group consisting of: 545, 570, 596, 601, 617, 623,624, 628, 630, 675, 685, 686, 696, and
 705. 17. The method of claim 16,wherein the at least one point mutation comprises (i) at least one pointmutation in a NTRK1 gene that results in the expression of a TrkA kinasepolypeptide comprising a mutation selected from the group consisting of:G517R, A542V, Q568x, V573M, F589L, F589C, G595S, G595R, F600L, R602x,F646V, C656Y, C656F, L657V, G667C, G667S, and Y676S, and/or (ii) atleast one point mutation in a NTRK2 gene that results in the expressionof a TrkB kinase polypeptide comprising a mutation selected from thegroup consisting of: G545R, A570V, Q596E, Q596P, V601G, F617L, F617C,F617I, G623S, G623R, D624V, F628x, R630K, F672x, C682Y, C682F, L683V,G693S, and Y702x, and/or (iii) at least one point mutation in a NTRK3gene that results in the expression of a TrkC kinase polypeptidecomprising a mutation at one or more amino acid position(s) selectedfrom the group consisting of: G545R, A570V, Q596x, F617L, G623R, D624V,F628x, R630x, F675x, C685Y, C685F, L686V, G696A, and Y705x.
 18. Themethod of claim 16, wherein the subject was previously administered oneor more doses of(S)—N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamidesulfate prior to being identified as having (i) at least one pointmutation in a NTRK1 gene that results in the expression of a TrkA kinasepolypeptide comprising a mutation at one or more amino acid position(s)selected from the group consisting of: 517, 542, 568, 573, 589, 595,599, 600, 602, 646, 656, 657, 667, and 676, and/or (ii) at least onepoint mutation in a NTRK2 gene that results in the expression of a TrkBkinase polypeptide comprising a mutation at one or more amino acidposition(s) selected from the group consisting of: 545, 570, 596, 601,617, 623, 624, 628, 630, 672, 682, 683, 693, and 702, and/or (iii) atleast one point mutation in a NTRK3 gene that results in the expressionof a TrkC kinase polypeptide comprising a mutation at one or more aminoacid position(s) selected from the group consisting of: 545, 570, 596,601, 617, 623, 624, 628, 630, 675, 685, 686, 696, and
 705. 19. Themethod of claim 18, wherein the at least one point mutation comprises(i) at least one point mutation in a NTRK1 gene that results in theexpression of a TrkA kinase polypeptide comprising a mutation selectedfrom the group consisting of: G517R, A542V, Q568x, V573M, F589L, F589C,G595S, G595R, F600L, R602x, F646V, C656Y, C656F, L657V, G667C, G667S,and Y676S, and/or (ii) at least one point mutation in a NTRK2 gene thatresults in the expression of a TrkB kinase polypeptide comprising amutation selected from the group consisting of: G545R, A570V, Q596E,Q596P, V601G, F617L, F617C, F617I, G623S, G623R, D624V, F628x, R630K,F672x, C682Y, C682F, L683V, G693S, and Y702x, and/or (iii) at least onepoint mutation in a NTRK3 gene that results in the expression of a TrkCkinase polypeptide comprising a mutation at one or more amino acidposition(s) selected from the group consisting of: G545R, A570V, Q596x,F617L, G623R, D624V, F628x, R630x, F675x, C685Y, C685F, L686V, G696A,and Y705x.
 20. The method of claim 16, wherein the Trk-associated canceris selected from the group consisting of: adenocarcinoma, adrenal glandcortical carcinoma, adrenal gland neuroblastoma, anus squamous cellcarcinoma, appendix adenocarcinoma, bladder urothelial carcinoma, bileduct adenocarcinoma, bladder carcinoma, bladder urothelial carcinoma,bone chordoma, bone marrow leukemia lymphocytic chronic, bone marrowleukemia non-lymphocytic acute myelocytic, bone marrow lymphproliferative disease, bone marrow multiple myeloma, bone sarcoma, brainastrocytoma, brain glioblastoma, brain medulloblastoma, brainmeningioma, brain oligodendroglioma, breast adenoid cystic carcinoma,breast carcinoma, breast ductal carcinoma in situ, breast invasiveductal carcinoma, breast invasive lobular carcinoma, breast metaplasticcarcinoma, cervix neuroendocrine carcinoma, cervix squamous cellcarcinoma, colon adenocarcinoma, colon carcinoid tumor, duodenumadenocarcinoma, endometrioid tumor, esophagus adenocarcinoma, eyeintraocular melanoma, eye intraocular squamous cell carcinoma, eyelacrimal duct carcinoma, fallopian tube serous carcinoma, gallbladderadenocarcinoma, gallbladder glomus tumor, gastroesophageal junctionadenocarcinoma, head and neck adenoid cystic carcinoma, head and neckcarcinoma, head and neck neuroblastoma, head and neck squamous cellcarcinoma, kidney chromophore carcinoma, kidney medullary carcinoma,kidney renal cell carcinoma, kidney renal papillary carcinoma, kidneysarcomatoid carcinoma, kidney urothelial carcinoma, leukemialymphocytic, liver cholangiocarcinoma, liver hepatocellular carcinoma,lung adenocarcinoma, lung adenosquamous carcinoma, lung atypicalcarcinoid, lung carcinosarcoma, lung large cell neuroendocrinecarcinoma, lung non-small cell lung carcinoma, lung sarcoma, lungsarcomatoid carcinoma, lung small cell carcinoma, lung small cellundifferentiated carcinoma, lung squamous cell carcinoma, lymph nodelymphoma diffuse large B cell, lymph node lymphoma follicular lymphoma,lymph node lymphoma mediastinal B-cell, lymph node lymphomaplasmablastic lung adenocarcinoma, lymphoma follicular lymphoma,non-Hodgkin's lymphoma, nasopharynx and paranasal sinusesundifferentiated carcinoma, ovary carcinoma, ovary carcinosarcoma, ovaryclear cell carcinoma, ovary epithelial carcinoma, ovary granulosa celltumor, ovary serous carcinoma, pancreas carcinoma, pancreas ductaladenocarcinoma, pancreas neuroendocrine carcinoma, peritoneummesothelioma, peritoneum serous carcinoma, placenta choriocarcinoma,pleura mesothelioma, prostate acinar adenocarcinoma, prostate carcinoma,rectum adenocarcinoma, rectum squamous cell carcinoma, skin adnexalcarcinoma, skin basal cell carcinoma, skin melanoma, skin Merkel cellcarcinoma, skin squamous cell carcinoma, small intestine adenocarcinoma,small intestine gastrointestinal stromal tumors (GISTs), soft tissueangiosarcoma, soft tissue Ewing sarcoma, soft tissuehemangioendothelioma, soft tissue inflammatory myofibroblastic tumor,soft tissue leiomyosarcoma, soft tissue liposarcoma, soft tissueneuroblastoma, soft tissue paraganglioma, soft tissue perivascularepitheliod cell tumor, soft tissue sarcoma, soft tissue synovialsarcoma, stomach adenocarcinoma, stomach adenocarcinoma diffuse-type,stomach adenocarcinoma intestinal type, stomach adenocarcinomaintestinal type, stomach leiomyosarcoma, thymus carcinoma, thymusthymoma lymphocytic, thyroid papillary carcinoma, unknown primaryadenocarcinoma, unknown primary carcinoma, unknown primary malignantneoplasm, unknown primary melanoma, unknown primary sarcomatoidcarcinoma, unknown primary squamous cell carcinoma, unknownundifferentiated neuroendocrine carcinoma, unknown primaryundifferentiated small cell carcinoma, uterus carcinosarcoma, uterusendometrial adenocarcinoma, uterus endometrial adenocarcinomaendometrioid, uterus endometrial adenocarcinoma papillary serous, anduterus leiomyosarcoma.